Bepotastine compositions

ABSTRACT

Novel compositions including bepotastine besilate and a corticosteroid are provided, compositions including at least about 0.008% w/v benzalkonium chloride, and compositions including hydroxypropylmethyl cellulose E15 LV.

This application claims priority to co-pending U.S. ProvisionalApplication Ser. No. 61/429,721 filed Jan. 4, 2011 which is expresslyincorporated by reference herein in its entirety.

BACKGROUND

Bepotastine,(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyricacid, is a non-sedating, highly selective antagonist of the histamine H1receptor. It has a stabilizing effect on mast cells, and it suppressesthe migration of eosinophils into inflamed tissues. It has threemechanisms of action: mast cell stabilizer, histamine antagonist, andmodulator/inhibitor of eosinophils. Bepotastine and pharmacologicallyacceptable salts thereof have an antihistaminic action and anantiallergic action. They are also characterized in that secondaryeffects such as stimulation or suppression of the central nerve oftenseen in the case of conventional antihistaminic agents can be minimized,and can be used as effective pharmaceutical agents for the treatment ofhuman and animals (PCT Patent Publication No. WO98/29409).

Bepotastine besilate has been approved in Japan for systemic use in thetreatment of allergic rhinitis since 2000 and urticaria/pruritus since2002. It is marketed in Japan by Mitsubishi Tanabe Pharma Corporation(formerly Tanabe Seiyaku Co., Ltd.) under the brand name TALION®. ISTAPharmaceuticals' eye drop formulation of bepotastine besilate, BEPREVE®(bepotastine besilate ophthalmic solution) 1.5% w/v, was approved by theU.S. Food and Drug Administration (FDA) in September 2009 for thetreatment of ocular itching associated with allergic conjunctivitis.

DETAILED DESCRIPTION THE INVENTION

Provided herein, inter alia, are novel compositions comprisingbepotastine as a free base, pharmaceutically acceptable salt, solvate,or physiologically functional derivative thereof, and at least onecorticosteroid as a free form, pharmaceutically acceptable salt,solvate, or physiologically functional derivative thereof, thecomposition which is effective for suppressing nasal inflammatoryconditions.

The present invention relates to the following.

[1] A pharmaceutical composition comprising at least one corticosteroidas a free form, pharmaceutically acceptable salt, solvate, orphysiologically functional derivative thereof, and bepotastine as a freebase, pharmaceutically acceptable salt, solvate or physiologicallyfunctional derivative thereof, the bepotastine at a concentration from0.5% w/v to 8.00% w/v inclusive, with at least one pharmaceuticallycompatible excipient, the composition formulated as a nasal spray.[2] The composition of [1] above wherein the bepotastine concentrationis from 2.00% w/v to 4.00% w/v inclusive.[3] The composition of any of [1]-[2] above wherein the excipient is aviscosity enhancing agent and is hydroxypropylmethyl cellulose (HPMC).[4] The composition of [3] above wherein the concentration of theviscosity enhancing agent is from 0.01% w/v-1.00% w/v.[5] The composition of any of [1]-[4] above further comprising apreservative.[6] The composition of [5] above wherein the preservative isbenzalkonium chloride.[7] The composition of any of [5]-[6] above wherein the concentration ofthe preservative is from 0.002% w/v-0.200% w/v.[8] The composition of any of [1]-[7] above further comprising at leastone pharmaceutically compatible buffer, a tonicity agent, a chelatingagent, a suspending agent, and an optional taste-masking agent.[9] The composition of [8] above wherein the pharmaceutically compatiblebuffer is each of a phosphate buffer and a citrate buffer.[10] The composition of [9] above wherein the phosphate buffer isdibasic sodium phosphate heptahydrate and the citrate buffer is citricacid monohydrate.[11] The composition of any of [8]-[10] above wherein the concentrationof the buffer is 0.10% w/v-1.00% w/v.[12] The composition of [8] above wherein the tonicity agent is sodiumchloride.[13] The composition of any of [8] or [12] above wherein theconcentration of the tonicity agent is 0.1% w/v-0.9% w/v.[14] The composition of [8] above wherein the chelating agent isethylenediamine tetraacetic acid.[15] The composition of any of [8] or [14] above wherein theconcentration of the chelating agent is 0.005% w/v-0.100% w/v.[16] The composition of [1] above wherein the excipient is a suspendingagent comprising a blend of microcrystalline cellulose and carboxymethylcellulose (AVICEL®) and/or polyoxyethylene (20) sorbitan monooleate(polysorbate 80).[17] The composition of [1] above wherein the excipient is a suspendingagent comprising HPMC, AVICEL®, and polysorbate 80.[18] The composition of any of [16]-[17] above wherein the concentrationof the suspending agent is 0.5% w/v-2.5% w/v for AVICEL® and is 0.005%w/v-0.050% w/v for polysorbate 80.[19] The composition of any of [16]-[18] above wherein AVICEL® isAVICEL® CL-611.[20] The composition of [8] above wherein the optional taste-makingagent is (tri)sodium citrate, sodium citrate, sodium chloride, sodiumbicarbonate, a polyol sweetener, a high intensity sweetener, and/or aflavoring agent.[21] The composition of any of [8] or [20] above wherein the optionaltaste-masking agent is sucralose.[22] The composition of any of [8], [20], or [21] above wherein theconcentration of the optional taste making agent is 0%-1.00% w/v.[23] The composition of any of [1]-[22] above where the pharmaceuticallyacceptable bepotastine salt is besilate.[24] The composition of any of [1]-[23] wherein the corticosteroidconcentration is from 0.01% w/v to 1% w/v inclusive, and thecorticosteroid is selected from the group consisting of beclomethasone,beclomethasone dipropionate, mometasone furoate monohydrate, fluticasonepropionate, fluticasone furoate, triamcinolone, triamcinolone acetonide,budesonide, budesonide free acid, ciclesonide, beclomethasone sodium,dexamethasone sodium, prednisolone acetate, and mixtures thereof.[25] A pharmaceutical composition comprising bepotastine besilate and acorticosteroid free form, pharmaceutically acceptable salt, solvate, orphysiologically functional derivative thereof, dibasic sodium phosphateheptahydrate, sodium chloride, edetate disodium, benzalkonium chloride,and one of either: a blend of microcrystalline cellulose andcarboxymethyl cellulose (AVICEL®) and/or polyoxyethylene (20) sorbitanmonooleate (polysorbate 80), or hydroxypropylmethyl cellulose (HPMC),citric acid monohydrate, and a taste making agent.[26] The composition of [25] above wherein the concentration ofbepotastine besilate is 0.5% w/v to 8.00% w/v; the concentration ofcorticosteroid is 0.01% w/v to 1.00% w/v; the concentration of dibasicsodium phosphate heptahydrate is 0.10% w/v to 1.00% w/v; theconcentration of sodium chloride is 0.9% w/v with 0.5% bepotastine, 0.4%w/v with 2.00%-3.00% bepotastine, 0.3% w/v with 4.00% bepotastine, 0.2%w/v with 6.00% bepotastine, 0.1% w/v with 8.00% bepotastine; theconcentration of edetate disodium is 0.005% w/v to 0.100% w/v; theconcentration of benzalkonium chloride is 0.002% w/v to 0.200% w/v; andif used, the concentration of AVICEL® CL-611 is 0.5% w/v to 2.5% w/v,and the concentration of polysorbate 80 is 0.005% w/v to 0.050% w/v; orif used, the concentration of HPMC is 0.01% w/v to 1.00% w/v, theconcentration of citric acid monohydrate is 0.10% w/v to 1.00% w/v, andthe concentration of the taste-making agent is 0.01% w/v to 1.00% w/v.[27] The composition of [25] above wherein the concentration ofbepotastine besilate is 4.00% w/v, the concentration of corticosteroidis 0.05% w/v, the concentration of dibasic sodium phosphate heptahydrateis 0.70% w/v, the concentration of sodium chloride is 0.30% w/v, theconcentration of edetate disodium is 0.020% w/v; the concentration ofbenzalkonium chloride is 0.020% w/v, and if used, the concentration ofAVICEL® CL-611 is 2.00% w/v and the concentration of polysorbate 80 is0.015% w/v; or if used, the concentration of HPMC E15 LV is 0.10% w/v,the concentration of citric acid monohydrate is 0.10% w/v, and thetaste-masking agent is sucralose and the concentration thereof is 0.10%w/v.[28] The composition of any of [25]-[27] above lacking substantialimpurities.[29] The composition of any of [25]-[28] above optionally containingsorbitol.[30] The composition of any of [25]-[29] above having pH 4-9.[31] The composition of any of [25]-[30] above containing AVICEL® CL-611and polysorbate 80 and having pH 6.4, or containing HPMC E15 LV, citricacid monohydrate, and a taste making agent and having pH 6.8.[32] Use of the composition of any of [25]-[31] above formulated fornasal administration to treat at least one of rhinitis, mucosalinflammation associated with rhinitis, sinusitis, rhinosinusitis, andsymptoms associated with rhinitis, mucosal inflammation associated withrhinitis, sinusitis, or rhinosinusitis.[33] The use of [32] above wherein rhinitis includes acute rhinitis,chronic rhinitis, allergic rhinitis, seasonal allergic rhinitis,perennial allergic rhinitis, vasomotor rhinitis, infectious rhinitis,and atrophic rhinitis.[34] The use of any of [32]-[33] above wherein the composition isformulated as a nasal spray, nasal drops, nasal droplets, orcombinations thereof.[35] The use of any of [32]-[34] above wherein the composition isnasally administered by a metered dose inhaler (MDI).[36] The use of [35] above wherein the MDI is any of a breath-actuatedMDI, a dry powder inhaler, a spacer/holding chambers in combination witha MDI, and a nebulizer.[37] The use of any of [35]-[36] above wherein the composition is in awet spray formulation or a dry spray formulation.[38] The use of any of [32]-[35] above wherein the composition isnasally administered by a metered dose plunger spray pump.[39] A method of treating at least one of rhinitis, mucosal inflammationassociated with rhinitis, sinusitis, rhinosinusitis, and symptomsassociated with rhinitis, mucosal inflammation associated with rhinitis,sinusitis, or rhinosinusitis in a patient in need of such treatment, themethod comprising nasally administering a pharmaceutical compositioncomprising a corticosteroid as a free form, pharmaceutically acceptablesalt, solvate or physiologically functional derivative thereof andbepotastine as a free base, pharmaceutically acceptable salt, solvate,or physiologically functional derivative thereof at a concentrationranging from 0.5% w/v to 8.00% w/v in aqueous solution to the patient inneed thereof, in a dose regimen effective to treat at least one ofrhinitis, mucosal inflammation associated with rhinitis, sinusitis,rhinosinusitis, and symptoms associated with rhinitis, mucosalinflammation associated with rhinitis, sinusitis, or rhinosinusitis.[40] The method of [39] above wherein bepotastine in the compositionadministered is at a concentration ranging from 2.00% w/v to 4.00% w/vand corticosteroid in the composition administered is at a concentrationranging from 0.01% w/v to 1% w/v.[41] The method of any of [39]-[40] above wherein administration is from1 time a day to 4 times a day.[42] The method of [41] above wherein bepotastine in the compositionadministered is at a concentration of either 3.00% w/v or 4.00% w/v andadministration is 1 time a day.[43] The method of [41] above wherein bepotastine in the compositionadministered is at a concentration of either 3.00% w/v or 4.00% w/v andadministration is at more than 12 hour intervals.[44] The method of any of [41]-[43] above wherein the dose regimen iseffective to treat allergic rhinitis.[45] The method of any of [39]-[44] above wherein the compositionadministered comprises

dibasic sodium phosphate heptahydrate at a concentration of 0.10% w/v to1.00% w/v;

sodium chloride at a concentration of 0.9% w/v with 0.5% bepotastine,0.4% w/v with 2.00%-3.00% bepotastine, 0.3% w/v with 4.00% bepotastine,0.2% w/v with 6.00% bepotastine, 0.1% w/v with 8.00% bepotastine;

edetate disodium at a concentration of 0.005% w/v to 0.100% w/v;

benzalkonium chloride at a concentration of 0.002% w/v to 0.200% w/v;and one of either:

a blend of microcrystalline cellulose and carboxymethyl cellulose(AVICEL®) at a concentration of 0.5% w/v to 2.5% w/v and polyoxyethylene(20) sorbitan monooleate (polysorbate 80) at a concentration of 0.005%w/v to 0.050% w/v, or

HPMC E15 LV at a concentration of 0.01% w/v to 1.00% w/v, citric acidmonohydrate at a concentration of 0.10% w/v to 1.00% w/v, and ataste-making agent at a concentration of 0.01% w/v to 1.00% w/v.

[46] The method of any of [39]-[44] above wherein the compositionadministered comprises dibasic sodium phosphate heptahydrate at aconcentration of 0.70% w/v, sodium chloride at a concentration of 0.30%w/v, edetate disodium at a concentration of 0.020% w/v, benzalkoniumchloride at a concentration of 0.020% w/v, and one of either: AVICEL® ata concentration of 2.00% w/v and polysorbate 80 at a concentration of0.015% w/v, or HPMC E15 LV at a concentration of 0.10% w/v, citric acidmonohydrate at a concentration of 0.10% w/v, and sucralose at aconcentration of 0.10% w/v.[47] The method of any of [39]-[46] above wherein the pharmaceuticallyacceptable salt of bepotastine is besilate.[48] The method of any of [45]-[46] above wherein AVICEL® is AVICEL®CL-611.[49] The method of any of [39]-[48] above wherein the corticosteroid isselected from the group consisting of beclomethasone, beclomethasonedipropionate, mometasone furoate monohydrate, fluticasone propionate,fluticasone furoate, triamcinolone, triamcinolone acetonide, budesonide,budesonide free acid, ciclesonide, beclomethasone sodium, dexamethasonesodium, prednisolone acetate, and mixtures thereof.[50] A kit comprising a metered dose plunger spray pump coupled with acontainer containing the composition of any of [1]-[31] above, andinstructions for administering the composition using the metered doseplunger spray pump.[51] A pharmaceutical composition comprising a pharmaceuticallyacceptable salt of bepotastine and at least one corticosteroid, dibasicsodium phosphate heptahydrate, sodium chloride, edetate disodium,benzalkonium chloride, a blend of microcrystalline cellulose andcarboxymethyl cellulose (AVICEL®), and/or polyoxyethylene (20) sorbitanmonooleate (polysorbate 80).[52] A pharmaceutical composition comprising a pharmaceuticallyacceptable salt of bepotastine and at least one corticosteroid, dibasicsodium phosphate heptahydrate, sodium chloride, edetate disodium,benzalkonium chloride, hydroxypropylmethyl cellulose (HPMC), citric acidmonohydrate, and a taste making agent.[53] The composition of [51] above wherein

the pharmaceutically acceptable salt of bepotastine is besilate and theconcentration of bepotastine is 0.5% w/v to 8.00% w/v;

the concentration of corticosteroid is 0.01% w/v to 1% w/v;

the concentration of dibasic sodium phosphate heptahydrate is 0.10% w/vto 1.00% w/v;

the concentration of sodium chloride is 0.9% w/v with 0.5% bepotastine,0.4% w/v with 2.00%-3.00% bepotastine, 0.3% w/v with 4.00% bepotastine,0.2% w/v with 6.00% bepotastine, 0.1% w/v with 8.00% bepotastine;

the concentration of edetate disodium is 0.005% w/v to 0.100% w/v;

the concentration of benzalkonium chloride is 0.002% w/v to 0.200% w/v;

the concentration of AVICEL® is 0.5% w/v to 2.5% w/v; and theconcentration of polysorbate 80 is 0.005% w/v to 0.050% w/v.

[54] The composition of [52] above wherein the pharmaceuticallyacceptable salt of bepotastine is besilate and the concentration ofbepotastine is 0.5% w/v to 8.00% w/v;

the concentration of corticosteroid is 0.01% w/v to 1% w/v;

the concentration of dibasic sodium phosphate heptahydrate is 0.10% w/vto 1.00% w/v;

the concentration of sodium chloride is 0.9% w/v with 0.5% bepotastine,0.4% w/v with 2.00%-3.00% bepotastine, 0.3% w/v with 4.00% bepotastine,0.2% w/v with 6.00% bepotastine, 0.1% w/v with 8.00% bepotastine;

the concentration of edetate disodium is 0.005% w/v to 0.100% w/v;

the concentration of benzalkonium chloride is 0.002% w/v to 0.200% w/v;

the concentration of HPMC E15 LV is 0.01% w/v to 1.00% w/v, theconcentration of citric acid monohydrate is 0.10% w/v to 1.00% w/v, andthe concentration of the taste-making agent is 0.01% w/v to 1.00% w/v.

[55] The composition of any of [51] or [53] above wherein theconcentration of bepotastine besilate is 4.00% w/v, the concentration ofcorticosteroid is 0.01% w/v to 1% w/v, the concentration of dibasicsodium phosphate heptahydrate is 0.70% w/v, the concentration of sodiumchloride is 0.30% w/v, the concentration of edetate disodium is 0.020%w/v, the concentration of benzalkonium chloride is 0.020% w/v, theconcentration of AVICEL® CL-611 is 2.00% w/v, and the concentration ofpolysorbate 80 is 0.015% w/v.[56] The composition of any of [52] or [54] above wherein theconcentration of bepotastine besilate is 4.00% w/v, the concentration ofcorticosteroid is 0.01% w/v to 1% w/v, the concentration of dibasicsodium phosphate heptahydrate is 0.70% w/v, the concentration of sodiumchloride is 0.30% w/v, the concentration of edetate disodium is 0.020%w/v, the concentration of benzalkonium chloride is 0.020% w/v, theconcentration of HPMC E15 LV is 0.10% w/v, the concentration of citricacid monohydrate is 0.10% w/v, and the taste-masking agent is sucraloseand the concentration thereof is 0.10% w/v.[57] The composition of any of [51]-[56] above lacking substantialimpurities.[58] The composition of any of [51]-[57] above optionally containingsorbitol.[59] The composition of any of [51]-[56] above having pH between pH 4.0to pH 9.0.[60] The composition of any of [51]-[56] above having pH between pH 5.0to pH 6.0.[61] The composition of any of [51]-[56] above having pH between pH 4.0to pH 5.5.[62] A pharmaceutical composition comprising a pharmaceuticallyacceptable salt of bepotastine and at least one corticosteroid, sodiumchloride, edetate disodium, benzalkonium chloride, a blend ofmicrocrystalline cellulose and carboxymethyl cellulose (AVICEL®), and/orpolyoxyethylene (20) sorbitan monooleate (polysorbate 80).[63] The composition of [62] above wherein the corticosteroid isfluticasone propionate and wherein the composition further comprisessodium phosphate dibasic heptahydrate and citric acid monohydrate,wherein the concentration of bepotastine besilate is 3.00% w/v, theconcentration of fluticasone propionate is 0.05% w/v, the concentrationof dibasic sodium phosphate heptahydrate is 0.70% w/v, the concentrationof sodium chloride is 0.60% w/v, the concentration of edetate disodiumis 0.020% w/v, the concentration of benzalkonium chloride is 0.0125%w/v, the concentration of citric acid monohydrate is 0.10% w/v, theconcentration of AVICEL® is 1.20% w/v, the concentration of polysorbate80 is 0.01% w/v, and the pH is adjusted to pH 5.0 to pH 7.0 with 2NNaOH.[64] The composition of [62] above wherein the corticosteroid isbudesonide free acid and wherein the composition further comprisessodium phosphate dibasic heptahydrate and citric acid monohydrate,wherein the concentration of bepotastine besilate is 3.00% w/v, theconcentration of budesonide is 0.05% w/v, the concentration of dibasicsodium phosphate heptahydrate is 0.70% w/v, the concentration of sodiumchloride is 0.60% w/v, the concentration of edetate disodium is 0.020%w/v, the concentration of benzalkonium chloride is 0.0125% w/v, theconcentration of citric acid monohydrate is 0.10% w/v, the concentrationof AVICEL® is 1.20% w/v, the concentration of polysorbate 80 is 0.01%w/v, and the pH is adjusted to pH 5.0 to pH 6.0 with 2N NaOH.[65] The composition of [62] above wherein the corticosteroid ismometasone furoate monohydrate and wherein the composition furthercomprises sodium phosphate dibasic heptahydrate and citric acidmonohydrate, wherein the concentration of bepotastine besilate is 3.00%w/v, the concentration of mometasone furoate monohydrate is 0.05% w/v,the concentration of dibasic sodium phosphate heptahydrate is 0.70% w/v,the concentration of sodium chloride is 0.60% w/v, the concentration ofedetate disodium is 0.020% w/v, the concentration of benzalkoniumchloride is 0.0125% w/v, the concentration of citric acid monohydrate is0.10% w/v, the concentration of AVICEL® is 1.20% w/v, the concentrationof polysorbate 80 is 0.01% w/v, and the pH is adjusted to pH 4.0 to pH5.5 with 2N NaOH.[66] The composition of [62] above wherein the corticosteroid istriamcinolone acetonide and wherein the composition further comprisessodium citrate, wherein the concentration of bepotastine besilate is4.00% w/v, the concentration of triamcinolone acetonide is 0.055% w/v,the concentration of sodium chloride is 0.30% w/v, the concentration ofedetate disodium is 0.020% w/v, the concentration of benzalkoniumchloride is 0.02% w/v, the concentration of sodium citrate is 0.40% w/v,the concentration of AVICEL® is 2.00% w/v, the concentration ofpolysorbate 80 is 0.015% w/v, and the pH is adjusted to pH 5.0 to pH 6.0with 2N NaOH.[67] The composition of [62] above wherein the corticosteroid isbeclomethasone dipropionate and wherein the composition furthercomprises sodium citrate, wherein the concentration of bepotastinebesilate is 4.00% w/v, the concentration of beclomethasone dipropionateis 0.05% w/v, the concentration of sodium chloride is 0.30% w/v, theconcentration of edetate disodium is 0.020% w/v, the concentration ofbenzalkonium chloride is 0.02% w/v, the concentration of sodium citrateis 0.40% w/v, the concentration of AVICEL® is 2.00% w/v, theconcentration of polysorbate 80 is 0.015% w/v, and the pH is adjusted topH 5.0 to pH 6.8 with 2N NaOH.[68] A pharmaceutical composition comprising at least one corticosteroidas a free form, pharmaceutically acceptable salt, solvate, orphysiologically functional derivative thereof, and bepotastine as a freebase, pharmaceutically acceptable salt, solvate or physiologicallyfunctional derivative thereof, the bepotastine at a concentration from0.5% w/v to 8.00% w/v inclusive, and a suspending agent interchangeablewith a viscosity enhancing agent, the composition formulated as a nasalspray.

The term “pharmaceutically acceptable salt” refers to salts derived froma variety of organic and inorganic counter ions well known in the artand any pharmaceutically acceptable salt soluble in water to form anaqueous solution. The term “effective amount” or “therapeuticallyeffective amount” refers to the amount of an active agent sufficient toinduce a desired biological result. That result may be alleviation ofthe signs, symptoms, or causes of a disease, or any other desiredalteration of a biological system. The term “therapeutically effectiveamount” is used herein to denote any amount of the formulation whichcauses a substantial improvement in a disease condition when applied tothe affected areas repeatedly over a period of time. The amount willvary with the condition being treated, the stage of advancement of thecondition, and the type and concentration of formulation applied.Appropriate amounts in any given instance will be readily apparent tothose skilled in the art or capable of determination by routineexperimentation.

As used herein, “treatment” or “treating,” or “palliating” or“ameliorating” are used interchangeably. These terms refer to anapproach for obtaining beneficial or desired results including but notlimited to therapeutic benefit and/or a prophylactic benefit. Bytherapeutic benefit is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forprophylactic benefit, the compositions may be administered to a patientat risk of developing a particular disease, or to a patient reportingone or more of the physiological symptoms of a disease, even though adiagnosis of this disease may not have been made. Treatment includespreventing the disease, that is, causing the clinical symptoms of thedisease not to develop by administration of a protective compositionprior to the induction of the disease; suppressing the disease, that is,causing the clinical symptoms of the disease not to develop byadministration of a protective composition after the inductive event butprior to the clinical appearance or reappearance of the disease;inhibiting the disease, that is, arresting the development of clinicalsymptoms by administration of a protective composition after theirinitial appearance; preventing re-occurring of the disease and/orrelieving the disease, that is, causing the regression of clinicalsymptoms by administration of a protective composition after theirinitial appearance.

A “subject,” “individual,” or “patient,” is used interchangeably herein,which refers to a vertebrate, preferably a mammal, more preferably ahuman. Mammals include, but are not limited to, murines, simians,humans, farm animals, sport animals, and pets. Tissues, cells and theirprogeny of a biological entity obtained in vitro or cultured in vitroare also encompassed.

The term “free,” “free of,” “substantially free,” or “substantially freeof,” as used herein, means present in quantities that have less than amaterial effect on, or confer less than a material advantage to, thepharmaceutical composition or one or more properties of thepharmaceutical composition (e.g., its preservative efficacy). In someembodiments, “free,” “free of,” “substantially free,” or “substantiallyfree of,” means not present.

The term “preservative efficacy” or “preservative effectiveness” or“antimicrobial efficacy”, as used herein, means that the compositionsatisfies USP standards as defined in protocol <51> p. 1681, UnitedStates Pharmacopeia, 1995: Antimicrobial effectiveness testing; TheUnited States Pharmacopeia, 32nd rev ed., and the National Formulary,27th ed. Rockville, Md.: USPC; 2009. For example, the preservative iseffective in the product examined if (a) the concentrations of viablebacteria are reduced to not more than 0.1% of the initial concentrationsby the fourteenth day; (b) the concentrations of viable yeasts and moldsremain at or below the initial concentrations during the first 14 days;and (c) the concentration of each test microorganism remains at or belowthese designated levels during the remainder of the 28-day test period.Similar criteria are defined for BP standards (Efficacy of AntimicrobialPreservation, Appendix XVI C, 1995), and PhEur standards (Efficacy ofAntimicrobial Preservation, Chapter VIII.14, 1992).

Provided herein, inter alia, are novel compositions comprisingbepotastine as a free base, a pharmaceutically acceptable salt ofbepotastine, e.g., bepotastine besilate, solvate or physiologicallyfunctional derivative thereof and a corticosteroid as a free form,pharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof. In some embodiments, the compositions are formulatedto provide a nasal composition, such as a nasal spray composition. Amongother aspects, the composition includes at least a preservative, e.g.,about 0.008% w/v benzalkonium chloride, and/or include a viscosityenhancing agent, e.g., a blend of microcrystalline cellulose andcarboxymethyl cellulose such as AVICEL®, or a hydroxypropylmethylcellulose (HPMC, Hypromellose (USAN)) such as HPMC E15 LV. In someembodiments, the compositions further include ethylenediaminetetraaceticacid or a salt thereof (e.g. EDTA or equivalent thereof). Accordingly,the compositions provided herein may have an acceptable shelf-life evenafter repeated use.

It has now been found that bepotastine as a free base, or apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof, can advantageously be combined with a corticosteroidas a free form, or a pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof, to provide a stable, veryeffective combination product or formulation preferably for nasal orocular treatment. The combination can provide, in a singleadministration or dosing regime, the antihistaminic properties ofbepotastine and the antiinflammatory (and/or other) properties of thesteroid, without any significant interference between the two, oradverse reaction in situ.

Thus, in one aspect, the present invention relates to a nasal spray as acombination of bepotastine with a corticosteroid to generally treatsymptoms of allergic or non-allergic rhinitis including nasal symptomsresulting from seasonal allergies and environmental irritants. Saidnasal spray may be used when the lining of the nose swells and releasesfluids which results in what is commonly referred to as “stuffy nose”.Also, in another aspect, the product or formulations of the presentinvention may be used to treat the symptoms of allergic conjunctivitis.

Among the corticosteroids useful for the nasal spray of this inventionare, for example, selected from the group consisting of beclomethasone,mometasone, fluticasone, triamcinolone, budesonide, ciclesonide,beclomethasone, dexamethasone, prednisolone, and combinations thereof.

Preferably, the concentration of bepotastine that is incorporated insaid nasal spray ranges from 0.5% w/v to 10% w/v, more preferably 2%w/v, 4% w/v, 6% w/v, or 8% w/v.

The corticosteroid concentration ranges from 0.01% w/v to 1% w/v,preferably 0.05% w/v, to thereby provide 10 mcg to 100 mcg, preferably50 mcg of corticosteroid per spray. The nasal spray may be used toprovide up to 8 sprays per day to treat the symptoms of allergic ornon-allergic rhinitis.

The nasal spray is preferably utilized as a liquid, but it may also beused in powder form.

Provided herein, inter alia, are novel compositions comprisingbepotastine besilate and a corticosteroid. In some embodiments, thecompositions are formulated to provide a nasal composition, such as anasal spray composition. Among other aspects, the compositions mayinclude at least about 0.008% w/v benzalkonium chloride, and/or includehydroxypropylmethyl cellulose E15 LV. In some embodiments, thecompositions further include ethylenediaminetetraacetic acid or a saltthereof (e.g. EDTA or equivalent thereof). Accordingly, the compositionsprovided herein may have an acceptable shelf-life even after repeateduse.

Further, additional enhanced properties can be achieved using thecompositions (e.g. nasal spray compositions) provided herein. Forexample, in some embodiments, the compositions provided herein have asubstantially uniform droplet size distribution (e.g., a Gaussian sizedistribution). Moreover, in some embodiments, the novel compositionsprovided herein have an acceptable taste despite the presence ofcomponents, such as bepotastine besilate, having unpleasant tastes.

Unless otherwise stated, all concentrations are in % w/v, and all rangesare inclusive (i.e., the upper and lower values are included within therange).

The first active ingredient for an antihistamine and/or antiallergyeffect of the compositions provided herein is(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino] butyricacid (bepotastine) having the following formula:

(I), including a derivative or a pharmaceutical acceptable saltsthereof.

The term “pharmaceutically acceptable salt” refers to salts derived froma variety of organic and inorganic counter ions well known in the artand includes any pharmaceutically acceptable salt soluble in water toform an aqueous solution. They include, by way of example only, basissalts, e.g. alkali metal salts such as sodium, potassium salts, alkalineearth metal salts such as calcium, magnesium, ammonium,tetraalkylammonium salts, and other metal salts such as strontium saltsand the like; and acid addition salts, e.g., inorganic acid additionsalts such as hydrochloride, hydrobromide, and organic acid additionsalts such as besilate, benzoate, toluenesulfonate, tartrate, mesylate,acetate, maleate, oxalate and the like; salts with hydrohalic acid suchas hydrochloride, hydrobromide and the like; salts with inorganic acidsuch as sulfate, nitrate, phosphate and the like; salts with organicacid such as acetate, propionate, hydroxyacetate, 2-hydroxypropionate,pyruvate, malonate, succinate, maleate, fumarate, dihydroxyfumarate,oxalate, benzoate, cinnamate, salicylate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate,cyclohexylsulfamate, 4-aminosalicylate and the like. The above-mentionedcompound to be used in the compositions provided herein is generallypreferably an acid addition salt, and of these acid addition salts,benzenesulfonate (besilate) and benzoate are more preferable. In someembodiments, the active ingredient of the compositions provided hereinis bepotastine besilate of the formula:

In some embodiments, the concentration of(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino] butyricacid, a pharmaceutically acceptable salt, solvate, or physiologicallyfunctional derivative thereof (e.g., bepotastine besilate) in thecomposition, calculated on the basis of molecular weight of the besilatesalt form of bepotastine, is from about 0.5% w/v to about 10% w/v (e.g.,about 0.5% w/v, about 1% w/v, about 2% w/v, about 3% w/v, about 4% w/v,about 5% w/v, about 6% w/v, about 7% w/v, about 8% w/v, about 9% w/v, orabout 10% w/v). In some embodiments, the compositions provided hereinhave a concentration of bepotastine besilate from about 5% w/v to about10% w/v. In some embodiments, the compositions provided herein have aconcentration of bepotastine besilate from about 10% w/v to about 20%w/v (e.g., about 10% w/v, about 11% w/v, about 12% w/v, about 13% w/v,about 14% w/v, about 15% w/v, about 16% w/v, about 17% w/v, about 18%w/v, about 19% w/v, or about 20% w/v). In some embodiments, thecompositions provided herein have more than 20% w/v bepotastinebesilate.

(+)-(S)-4-[4-[(4-Chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acidor a pharmaceutically acceptable salt thereof can be produced by, forexample, the methods described in PCT Patent Publication Nos.WO98/29409, WO2008/123701, WO2009/075504 and the like.

The second active ingredient is a corticosteroid which is useful forsuppressing inflammatory conditions, e.g. nasal inflammatory conditions.The corticosteroid may be a free form or may be a pharmaceuticallyacceptable salt, solvate, or physiologically functional derivativethereof. The pharmaceutically acceptable salts of corticosteroid includesodium salt. The solvate includes a hydrate. The physiologicallyfunctional derivatives include esters with a lower alkanoic acid (e.g.,acetic acid, propionic acid), furancarboxylic acid and the like;acetonide. Preferable examples include beclomethasone, beclomethasonedipropionate, mometasone furoate monohydrate, fluticasone propionate,fluticasone furoate, triamcinolone, triamcinolone acetonide, budesonide,ciclesonide, beclomethasone sodium, dexamethasone sodium, prednisoloneacetate, and mixtures thereof.

In some embodiments, the concentration of a corticosteroid free form, apharmaceutically acceptable salt, solvate, or physiologically functionalderivative thereof in the composition, calculated on the basis ofmolecular weight of the respective anhydrous salt form ofcorticosteroid, is from about 0.01% w/v to about 1% w/v.

The compositions provided herein may include an effective amount of anantimicrobial preservative. Preservatives can be used to inhibitmicrobial growth (e.g., bacterial or yeast) in the compositions. An“effective amount” of a preservative is that amount necessary to preventthe growth of microorganisms in the composition. In some embodiments,the concentration or amount of preservative is generally that which isnecessary to prevent microbial growth in the composition for a storageperiod of at least six months. In certain embodiments, the concentrationor amount of preservative is that which is necessary to satisfy USPstandards as defined in protocol <51> p. 1681, United StatesPharmacopeia, 1995, Antimicrobial effectiveness testing; The UnitedStates Pharmacopeia, 32nd rev ed., and the National Formulary, 27th ed.Rockville, Md.: USPC; 2009.

Examples of pharmaceutically acceptable preservatives includebenzethonium chloride, butylparaben, methyl paraben, ethyl paraben,propyl paraben, benzalkonium chloride, cetyl pyridinium chloride,thimerosal, chlorobutanol, phenylethyl alcohol, benzyl alcohol,potassium sorbate, sodium benzoate, sorbic acid, oxychloro complexes(otherwise known as PURITE®), phenylmercuric acetate, chlorobutanol,benzyl alcohol, parabens, and thimerosal or combinations thereof. Insome embodiments, the preservative is benzalkonium chloride (BAK). Insome embodiments, the compositions include a preservative in combinationwith a chelating agent, as set forth below.

In one embodiment, the antimicrobial preservative (e.g. benzalkoniumchloride) may be present in the composition in an amount of from about0.002% w/v to about 0.200% w/v. In another embodiment, the antimicrobialpreservative (e.g. benzalkonium chloride) may be present in thecomposition in an amount of from about 0.005% w/v to about 0.100% w/v.In yet another embodiment, the antimicrobial preservative (e.g.benzalkonium chloride) may be present in the composition in an amount offrom about 0.010% w/v to about 0.050% w/v.

In some embodiments, the preservative in the composition is benzalkoniumchloride. In some embodiments, benzalkonium chloride may be present inthe composition in an amount of from about 0.008% w/v to about 0.015%w/v. In some embodiments, the compositions provided herein have aconcentration of benzalkonium chloride from about 0.008% w/v to about0.010% w/v, from about 0.010% w/v to about 0.012% w/v, from about 0.012%w/v to about 0.015% w/v, or more than 0.015% w/v. In some embodiments,the compositions provided herein have about 0.008% w/v, about 0.009%w/v, about 0.010% w/v, about 0.0011% w/v, about 0.012% w/v, about 0.013%w/v, about 0.014% w/v, or about 0.015% w/v benzalkonium chloride. Insome embodiments, the compositions provided herein include only a singlepreservative. In some embodiments, the compositions provided hereininclude only two preservatives.

The compositions provided herein can include an effective amount of achelating agent. The term “chelating agent” refers to a compound ormixture of compounds used in a formulation that is capable of complexinga metal, as understood by those of ordinary skill in the chemical art.Chelating agents complex metal ions such as iron, copper and lead, andmay act as antioxidant synergist as otherwise these heavy metalscatalyze oxidation reactions. Presently preferred chelating agentsnon-exclusively include different salts of edetic acid. Thesenonexclusively include edetate disodium, edetate calcium disodium,edetate tetrasodium, edetate trisodium, and combinations thereof. In oneembodiment, the chelating agent may be present in the composition in anamount of from about 0.005% w/v to about 0.100% w/v. In anotherembodiment, the chelating agent may be present in the composition in anamount of from about 0.010% w/v to about 0.050% w/v. In yet anotherembodiment, the chelating agent may be present in the composition in anamount of from about 0.010% w/v to about 0.020% w/v.

In some embodiments, the chelating agent in the composition isethylenediaminetetraacetic acid or a salt thereof. In some embodiments,benzalkonium chloride may be present in the composition in an amount offrom about 0.002% w/v to about 0.200% w/v. In some embodiments, thecompositions provided herein have a concentration ofethylenediaminetetraacetic acid or a salt thereof from about 0.002% w/vto about 0.010% w/v, from about 0.010% w/v to about 0.050% w/v, fromabout 0.050% w/v to about 0.200% w/v, or more than 0.200% w/v. In someembodiments, the compositions provided herein have about 0.005% w/v,about 0.010% w/v, about 0.020% w/v, about 0.030% w/v, or about 0.040%w/v ethylenediaminetetraacetic acid or a salt thereof. In someembodiments, the compositions provided herein include only a chelatingagent.

The compositions provided herein can include an effective amount of aviscosity agent. The term “viscosity agent,” or “viscosity enhancingagent”, as used herein, refers to molecular species in the compositionsprovided herein that increase the viscosity of the composition.Preferred viscosity enhancing agents include, e.g., polyols, polymers,sugars, and polysaccharides. In some embodiments, the viscosity agenthas a viscosity of 2% solution in water of about 12-18 mPA·s (USP/EP/JP)

It will be appreciated by one skilled in the art that viscosity agentsmay also be suspending agents, and that suspending agents may also beviscosity agents.

In some embodiments, the viscosity agent in the composition ishydroxypropylmethyl cellulose E15 LV (HPMC E15 LV) (a water-solublecellulose ether having a methoxyl content of about 28-30%, ahydroxypropoxyl content of about 7-12%, and a viscosity of 2% solutionin water of about 12-18 mPA·s (USP/EP/JP), available from Dow asMETHOCEL®). In some embodiments, HPMC E15 LV may be present in thecomposition in an amount of from about 0.01% w/v to about 1.00% w/v. Insome embodiments, the compositions provided herein have a concentrationof HPMC E15 LV from about 0.01% w/v to about 0.05% w/v, from about 0.05%w/v to about 0.10% w/v, from about 0.10% w/v to about 0.50% w/v, fromabout 0.50% w/v to about 1.00% w/v, or more than 1.00% w/v. In someembodiments, the compositions provided herein have about 0.02% w/v,about 0.05% w/v, about 0.10% w/v, about 0.20% w/v, or about 0.30% w/vHPMC E15 LV. In some embodiments, the compositions provided hereininclude only a single viscosity agent.

In some embodiments, the viscosity agent in the composition facilitatesmore or less uniform dispersement of the active ingredient in a liquid,that is, it is a suspending agent. Such an agent provides for increasedor optimized residence time of the active ingredient in nasal tissue andminimized agent ingredient outside nasal tissue (e.g., in the throat),while beneficially providing thixotropic properties that still permitexpression of the composition from a spray or other administrationorifice. Examples of such suspending agents include a blend ofmicrocrystalline cellulose and carboxymethyl cellulose, e.g., AVICEL®(FMC), e.g., AVICEL® CL-611, AVICEL® RC-581, AVICEL® RC-591, and otherpharmaceutically acceptable thixotropic agents. AVICEL® CL-611 andAVICEL® RC-591 are examples of strong suspending agents. According tothe manufacturer, AVICEL® CL-611 is similar to AVICEL® RC-591. AVICEL®CL-611 is more compatible with a higher concentration of salts insolution, while the viscosity and suspension properties of AVICEL®RC-591 are more sensitive to the amount of salts in solution. AVICEL®CL-611 also imparts a physical property of viscosity, so is consideredas both a suspending agent and a viscosity enhancing agent. In oneembodiment, the concentration of AVICEL® CL-611 is from 0.5% w/v to 2.5%w/v. In one embodiment, the concentration of AVICEL® CL-611 is 2.00%w/v. Another example of a suspending agent is a polyoxyethylene (20)sorbitan monooleate (polysorbate 80), e.g., at 0.005% w/v to 0.050% w/v;in one embodiment at 0.015% w/v.

In one embodiment in formulating a disclosed composition, AVICEL® wasdissolved in about 75% of the water with high speed mixing for aboutfive minutes. Polysorbate 80 was mixed with a small portion of the waterand was added to the AVICEL® solution and mixed at high speed for aboutfive minutes. Sodium phosphate was added to the resulting mixture withmixing, followed by a tonicity agent (e.g., sodium chloride), achelating agent (e.g., EDTA) and bepotastine besilate andcorticosteroid. The pH was adjusted with NaOH. A preservative (e.g.,benzalkonium chloride) was added last, followed by the addition of waterto 100%.

The compositions provided herein may optionally include an effectiveamount of a taste masking agent. In some embodiments, formulations ofbepotastine in the presence of a corticosteroid do not contain ataste-masking agent. The taste-masking agent is one or more agents orcompounds which, optionally together, successfully mask or cover the(potential) unpleasant taste of one or more components of thecompositions provided herein when present in an effective amount. Insome embodiments, the compositions comprise two or more taste maskingagents, such as a polyol sweetener and a high intensity sweetener. Insome embodiments, the compositions include only a single taste maskingagent in the absence of any other sweeteners, flavorants or tastemasking agents.

In some embodiments, the taste masking agent is (tri)sodium citrate,sodium citrate, sodium chloride, sodium bicarbonate, and combinationsthereof.

In some embodiments, the taste masking agent is a polyol sweetener. Aspecific example of one category of polyol sweeteners include sugars, inparticular a sugar selected from the group consisting of dextrose,sucrose, maltose, fructose, lactose, and combinations thereof. Anotherspecific example of another category of polyol sweeteners include sugaralcohols, in particular sugar alcohols selected from the groupconsisting of xylitol, sorbitol, mannitol, maltitol, isomaltol, isomalt,erythritol, lactitol, maltodextrin, hydrogenated starch hydrolysates,D-xylose, trehalose, and combinations thereof.

In some embodiments, the taste masking agent is a high intensitysweetener or a flavor. Useful high intensity sweeteners may be selectedfrom the group consisting of sucralose, neotame, aspartame, salts ofacesulfame in particular the potassium salt of acesulfame (acesulfameK), alitame, saccharin and its salts, cyclamic acid and its salts,glycyrrhizin, dihydrochalcones e.g. NHDC, thaumatin, monellin,stevioside, Twinsweet (aspartame-acesulfame salt) and combinationsthereof. Still other examples of suitable taste masking agents includesalts of gluconate, such as sodium gluconate.

In some embodiments, the taste-masking agent is one or more flavoringagents, optionally in combination with one or more food acids. Flavorswhich can be used in the compositions according to the present inventioninclude, but are not limited to, coconut, coffee, cola, chocolate,vanilla, orange, lemon, grape fruit, menthol, licorice, anise, apricot,caramel, honey, pineapple, strawberry, raspberry, tropical fruits,cherries, cinnamon, peppermint, wintergreen, spearmint, eucalyptus andmint flavors. In one embodiment, the flavors are chosen from menthol,caramel, coffee, cola, and combinations thereof, in particular thecombination of menthol and caramel.

In some embodiments, the taste-masking agent in the compositions issucralose (e.g. in the absence of other sweeteners, flavorants or tastemasking agents). In some embodiments, sucralose may be present in thecomposition in an amount of from about 0.01% w/v to about 1.00% w/v. Insome embodiments, the compositions provided herein have a concentrationof sucralose from about 0.01% w/v to about 0.05% w/v, from about 0.05%w/v to about 0.10% w/v, from about 0.10% w/v to about 0.50% w/v, fromabout 0.50% w/v to about 1.00% w/v, or more than 1.00% w/v. In someembodiments, the compositions provided herein have about 0.02% w/v,about 0.05% w/v, about 0.10% w/v, about 0.20% w/v, or about 0.30% w/v ofsucralose.

The compositions provided herein can further include other ingredientsand components such as a tonicity agent or a buffer. The term “tonicityagent,” as used herein, denotes pharmaceutically acceptable tonicityagents. Tonicity agents are used to modulate the tonicity of theformulation. The formulation can be hypotonic, isotonic or hypertonic.Isotonicity in general relates to the osmotic pressure of a solutionusually relative to that of human blood serum. The formulation accordingto the invention can be hypotonic, isotonic or hypertonic but willpreferably be isotonic. An isotonic formulation is liquid or liquidreconstituted from a solid form, e.g. from a lyophilised form anddenotes a solution having the same tonicity as some other solution withwhich it is compared, such as physiologic salt solution and the bloodserum. Suitable tonicity agents comprise but are not limited to metalchloride (e.g., sodium chloride, potassium chloride), glycerine and anycomponent from the group of amino acids, sugars, in particular glucose.Tonicity agents are generally used in an amount of about 5 mM to about500 mM. In a preferred formulation the amount of tonicity agent is inthe range of about 50 mM to about 300 mM. In some embodiments, thecompositions provided herein include only a tonicity agent (e.g. sodiumchloride).

In some embodiments, the tonicity agent in the composition is sodiumchloride. In some embodiments, sodium chloride may be present in thecomposition in an amount of from about 0.10% w/v to about 1.00% w/v. Insome embodiments, the compositions provided herein have a concentrationof sodium chloride from about 0.10% w/v to about 0.20% w/v, from about0.20% w/v to about 0.50% w/v, from about 0.50% w/v to about 0.75% w/v,from about 0.75% w/v to about 1.00% w/v, or more than 1.00% w/v. In someembodiments, the compositions provided herein have about 0.20% w/v,about 0.30% w/v, about 0.40% w/v, about 0.50% w/v, or about 0.70% w/vsodium chloride.

The term “buffer” as used herein denotes a pharmaceutically acceptableexcipient, which stabilizes the pH of a pharmaceutical preparation.Preferred pharmaceutically acceptable buffers comprise but are notlimited to borate-buffers, histidine-buffers, citrate-buffers,succinate-buffers, acetate-buffers, tartrate-buffers, andphosphate-buffers. The abovementioned buffers are generally used in anamount of about 1 mM to about 100 mM, preferably of about 5 mM to about50 mM and more preferably of about 10 mM-20 mM.

In some embodiments, the buffer in the composition is citric acid (e.g.citric acid monohydrate) and/or sodium phosphate (e.g. sodium phosphatedibasic heptahydrate). In some embodiments, the citric acid and/orsodium phosphate buffers may be present in the composition in an amountof from about 0.10% w/v to about 1.00% w/v. In some embodiments, thecompositions provided herein have a concentration of citric acid orsodium phosphate from about 0.10% w/v to about 0.20% w/v, from about0.20% w/v to about 0.50% w/v, from about 0.50% w/v to about 0.75% w/v,from about 0.75% w/v to about 1.00% w/v, or more than 1.00% w/v. In someembodiments, the compositions provided herein have about 0.20% w/v,about 0.30% w/v, about 0.40% w/v, about 0.50% w/v, or about 0.70% w/vcitric acid or sodium phosphate.

The pH can be adjusted at a value of from about 4.0 to about 9.0 andpreferably about 5.0 to about 8.0 and still preferably about 6.0 toabout 7.0 with an acid or a base as known in the art, e.g. hydrochloricacid, acetic acid, phosphoric acid, sulfuric acid and citric acid,sodium hydroxide and potassium hydroxide. The pH of the compositionsprovided herein is adjusted to not less than about 4.0, 5.0, or 6.0, andnot more than about 8.5, 8.0, or 9.0. In some embodiments, thecompositions provided herein include only a buffer. In otherembodiments, the compositions provided herein include only two buffers.

The compositions provided herein may include a solvent. In someembodiments, the solvent is water. In some embodiments, the compositionsprovided herein include only a single solvent (e.g. water). In thecompositions provided herein, other similar or non-similar efficaciousingredients may be added appropriately in a manner avoiding impairmentof the object of the present invention.

Provided herein are compositions (e.g. nasal compositions such as nasalspray compositions) including(+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acidas a free base, pharmaceutical acceptable salt, solvate, orphysiologically functional derivative thereof, and a corticosteroid as afree form, pharmaceutically acceptable salt, solvate, or physiologicallyfunctional derivative thereof, in combination with a preservative,optionally a chelating agent, optionally a viscosity agent, optionally ataste masking agent, and optionally a tonicity agent and a buffer, asdescribed above. In some embodiments, the invention relates to acomposition comprising bepotastine besilate and a corticosteroid.

In some embodiments, the composition comprises bepotastine besilate anda corticosteroid, and may further include a preservative, e.g.,benzalkonium chloride. In some embodiments, the composition includes atleast about 0.008% w/v benzalkonium chloride. In some embodiments, thecomposition includes at least about 0.010% w/v benzalkonium chloride. Insome embodiments, the composition includes at least about 0.0125% w/vbenzalkonium chloride. The composition may further include a chelatingagent, such as ethylenediaminetetraacetic acid or a salt thereof. Insome embodiments, the composition includes from about 0.002% w/v toabout 0.200% w/v ethylenediaminetetraacetic acid or a salt thereof. Insome embodiments, the composition includes about 0.02% w/vethylenediaminetetraacetic acid or a salt thereof. The composition mayfurther include a viscosity agent, e.g., hydroxypropylmethyl celluloseE15 LV. In some embodiments, the composition includes from about 0.01%w/v to about 1.00% w/v hydroxypropylmethyl cellulose E15 LV. In someembodiments, the composition includes about 0.10% w/vhydroxypropylmethyl cellulose E15 LV. The composition may furtherinclude a taste masking agent, e.g., sucralose. In some embodiments, thecomposition includes from about 0.01% w/v to about 1.00% w/v sucralose.In some embodiments, the composition includes about 0.10% w/v sucralose.In some embodiments, the concentration of bepotastine besilate is fromabout 0.5% w/v to about 10% w/v. In some embodiments, the concentrationof bepotastine besilate is about 2% w/v. In some embodiments, theconcentration of bepotastine besilate is about 4% w/v. In someembodiments, the concentration of bepotastine besilate is about 6% w/v.In some embodiments, the concentration of bepotastine besilate is about8% w/v.

In some embodiments, the nasal composition includes bepotastine besilateand a corticosteroid, and at least about 0.008% w/v benzalkoniumchloride. In some embodiments, the composition includes at least about0.008% w/v benzalkonium chloride. In some embodiments, the compositionincludes at least about 0.010% w/v benzalkonium chloride. In someembodiments, the composition includes at least about 0.0125% w/vbenzalkonium chloride. The composition may further include a chelatingagent, such as ethylenediaminetetraacetic acid or a salt thereof. Insome embodiments, the composition includes from about 0.002% w/v toabout 0.200% w/v ethylenediaminetetraacetic acid or a salt thereof. Insome embodiments, the composition includes about 0.02% w/vethylenediaminetetraacetic acid or a salt thereof. The composition mayfurther include a viscosity agent, e.g., hydroxypropylmethyl celluloseE15 LV. In some embodiments, the composition includes from about 0.01%w/v to about 1.00% w/v hydroxypropylmethyl cellulose E15 LV. In someembodiments, the composition includes about 0.10% w/vhydroxypropylmethyl cellulose E15 LV. The composition may furtherinclude a taste masking agent, e.g., sucralose. In some embodiments, thecomposition includes from about 0.01% w/v to about 1.00% w/v sucralose.In some embodiments, the composition includes about 0.10% w/v sucralose.In some embodiments, the concentration of bepotastine besilate is fromabout 0.5% w/v to about 10% w/v. In some embodiments, the concentrationof bepotastine besilate is about 2% w/v. In some embodiments, theconcentration of bepotastine besilate is about 4% w/v. In someembodiments, the concentration of bepotastine besilate is about 6% w/v.In some embodiments, the concentration of bepotastine besilate is about8% w/v.

In some embodiments, the nasal composition includes bepotastine besilateand a corticosteroid and hydroxypropylmethyl cellulose E15 LV. In someembodiments, the composition includes from about 0.01% w/v to about1.00% w/v hydroxypropylmethyl cellulose E15 LV. In some embodiments, thecomposition includes about 0.10% w/v hydroxypropylmethyl cellulose E15LV. The composition may further include a preservative, e.g.,benzalkonium chloride. In some embodiments, the composition includes atleast about 0.008% w/v benzalkonium chloride. In some embodiments, thecomposition includes at least about 0.010% w/v benzalkonium chloride. Insome embodiments, the composition includes at least about 0.0125% w/vbenzalkonium chloride. The composition may further include a chelatingagent, such as ethylenediaminetetraacetic acid or a salt thereof. Insome embodiments, the composition includes from about 0.002% w/v toabout 0.200% w/v ethylenediaminetetraacetic acid or a salt thereof. Insome embodiments, the composition includes about 0.02% w/vethylenediaminetetraacetic acid or a salt thereof. The composition mayfurther include a taste masking agent, e.g., sucralose. In someembodiments, the composition includes from about 0.01% w/v to about1.00% w/v sucralose. In some embodiments, the composition includes about0.10% w/v sucralose. In some embodiments, the concentration ofbepotastine besilate is from about 0.5% w/v to about 10% w/v. In someembodiments, the concentration of bepotastine besilate is about 2% w/v.In some embodiments, the concentration of bepotastine besilate is about4% w/v. In some embodiments, the concentration of bepotastine besilateis about 6% w/v. In some embodiments, the concentration of bepotastinebesilate is about 8% w/v.

In some embodiments, the nasal composition includes bepotastine besilateand a corticosteroid, at least about 0.008% w/v benzalkonium chloride,and hydroxypropylmethyl cellulose E15 LV. In some embodiments, thecomposition further includes ethylenediaminetetraacetic acid or a saltthereof. In some embodiments, the composition further includes a tastemasking agent, e.g., sucralose. In some embodiments, the concentrationof bepotastine besilate is from about 0.5% to about 10% w/v. In someembodiments, the concentration of bepotastine besilate is about 2% w/v.In some embodiments, the concentration of bepotastine besilate is about4% w/v. In some embodiments, the concentration of bepotastine besilateis about 6% w/v. In some embodiments, the concentration of bepotastinebesilate is about 8% w/v.

In some embodiments, the nasal composition includes about 0.0125% w/vbenzalkonium chloride, about 0.1% w/v hydroxypropylmethyl cellulose E15LV, about 0.1% sucralose, about 0.02% w/v ethylenediaminetetraaceticacid or a salt thereof. In some embodiments, the concentration ofbepotastine besilate is from about 0.5% w/v to about 10% w/v. In someembodiments, the concentration of bepotastine besilate is about 2% w/v.In some embodiments, the concentration of bepotastine besilate is about4% w/v. In some embodiments, the concentration of bepotastine besilateis about 6% w/v. In some embodiments, the concentration of bepotastinebesilate is about 8% w/v.

In some embodiments, the nasal composition contains only bepotastinebesilate and a corticosteroid, citric acid, sodium phosphate, metalchloride, sucralose, hydroxypropylmethyl cellulose,ethylenediaminetetraacetic acid or a salt thereof, about 0.008% w/v toabout 0.015% w/v benzalkonium chloride, sodium hydroxide and water. Insome embodiments, the metal chloride is sodium chloride. In someembodiments, the hydroxypropylmethyl cellulose is hydroxypropylmethylcellulose E15 LV. In some embodiments, the nasal composition consists ofbepotastine besilate, citric acid, sodium phosphate, metal chloride,sucralose, hydroxypropylmethyl cellulose, ethylenediaminetetraaceticacid or a salt thereof, about 0.0125% w/v to about 0.015% w/vbenzalkonium chloride, sodium hydroxide and water. In some embodiments,the concentration of bepotastine besilate is from about 0.5% w/v toabout 10% w/v. In some embodiments, the concentration of bepotastinebesilate is about 2% w/v. In some embodiments, the concentration ofbepotastine besilate is about 4% w/v. In some embodiments, theconcentration of bepotastine besilate is about 6% w/v. In someembodiments, the concentration of bepotastine besilate is about 8% w/v.

A person having ordinary skill in the art will recognize that, in someembodiments, components of the compositions detailed above, except theactive ingredients, namely, bepotastine and corticosteroid, may beremoved or replaced in keeping with known practices in the art ofpharmaceutical formulations.

Provided herein are methods of treating rhinitis, mucosal inflammationassociated with rhinitis, sinusitis, and/or symptoms associated thereto.Nasal symptoms include symptoms known to be problematic for patientswith rhinitis or sinusitis: nasal itching, rhinorrhea (runny nose),nasal congestion (stuffy nose), and sneezing. As used herein, the term“rhinitis” refers to inflammation of the nasal mucous membranesresulting from, e.g., a cold, flu, or allergies. Rhinitis may becharacterized by one or more cold-like symptoms including, for example,rhinorrhea, sneezing, nasal congestion, and increased nasal secretion.Rhinitis can include acute rhinitis, chronic rhinitis, allergicrhinitis, seasonal allergic rhinitis, perennial allergic rhinitis,vasomotor rhinitis, infectious rhinitis, and atrophic rhinitis. As usedherein, the term “sinusitis” refers to inflammation of the paranasalsinuses, which can be the result of infection (e.g., bacterial, fungalor viral), allergic or autoimmune causes. It should be appreciated thatnewer classifications of sinusitis may refer to the condition as“rhinosinusitis” since inflammation of the sinuses typically does notoccur without some inflammation of the nose as well.

According to the present invention, rhinitis may generally include anyinflammation of the nasal mucous membrane. Symptoms of rhinitis cangenerally include one or more cold-like symptoms including, for example,rhinorrhea, increased nasal secretion, nasal congestion, sneezing andcatarrh. Rhinitis can also include both allergic rhinitis andnon-allergic rhinitis. “Allergic rhinitis” refers to any allergicreaction of the nasal mucosa and may include hay fever (seasonalallergic rhinitis) and perennial rhinitis (non-seasonal allergicrhinitis). “Non-allergic rhinitis” refers to eosinophilic non-allergicrhinitis which is found in subjects with negative skin tests and thosewho have numerous eosinophils in their nasal secretions. In someembodiments, the compositions provided herein are useful in treatingallergic rhinitis.

Sinusitis can include a condition that is similar to rhinitis generallycharacterized by inflammation of the paranasal sinuses. Sinusitis can beacute (i.e., less than four weeks), subacute (i.e., 4-12 weeks) orchronic (i.e., for 12 weeks or more), and can include such symptoms asheadache, upper jaw and teeth pain, swelling of the eyelids and oculartissue, and superficial pain associated with tactile compression of thenose.

For nasal administration of the nasal compositions, various devices areavailable in the art for the generation of drops, droplets and sprays.For example, the nasal spray composition can be administrated into thenasal passages of a subject by means of a dropper (or pipet) thatincludes a glass, plastic or metal dispensing tube. Fine droplets andsprays can be provided by an intranasal pump dispenser or squeeze bottleas well known in the art.

Other means for delivering the nasal compositions, such as inhalationvia a metered dose inhaler (MDI), may also be used according to thepresent invention. Several types of MDIs are regularly used foradministration by inhalation. These types of devices can includebreath-actuated MDI, dry powder inhaler (DPI), spacer/holding chambersin combination with MDI, and nebulizers. The term “MDI” as used hereinrefers to an inhalation delivery system comprising, for example, acanister containing an active agent dissolved or suspended in apropellant optionally with one or more excipients, a metered dose valve,an actuator, and a mouthpiece. The canister is usually filled with asolution or suspension of an active agent, such as the nasal spraycomposition, and a propellant, such as one or more hydrofluoroalkanes.When the actuator is depressed a metered dose of the solution isaerosolized for inhalation. Particles comprising the active agent(s) arepropelled toward the mouthpiece where they may then be inhaled by asubject.

Either aqueous or “wet” spray formulations, or pressurized, non-aqueousaerosol “dry” spray formulations propelled by hydrofluoroalkane may beused, either of which may contain a built-in dose counter.

In one embodiment, the delivery system is a metered dose plunger spraypump. The pump and actuator are commercially available (Aptar (Valois))(pump: VP7A/100 CS-20-AG 908EVAE2 EM24, 100 μL spray, 20 mm crimp, 24 mmdip tube length; polypropylene (PP) body, 11R51 or 12R10 stainless steelspring, ethylene vinyl acetate (EVA) gasket, aluminum ferrule)(actuator: CB18 NAC/3/B Bepaule+CAP B25A, polypropylene body). In oneembodiment, the pump is coupled to a neck of a container containing thepharmaceutical bepotastine besilate composition. Coupling methodsinclude, but are not limited to, a crimp-seal to the container, atorqued coupling onto matching threads of the container, depression of asnap-cap pump into place with the container, etc. The above deliverysystem may be physically modified, e.g., to accommodate specific bottlesfor a nasal spray composition, etc. In one embodiment, a kit containsthe pump, container, and instructions for use to treat a patient withthe disclosed bepotastine besilate composition.

After appropriately packaging the nasal spray composition in a squeezebottle, for example, the nasal composition may be intranasallyadministered to one or both nasal cavities of the subject at a desireddosage. For example, the plastic dispensing tube may be appropriatelyplaced in one nostril of the subject. The squeeze bottle may then besqueezed so that the nasal spray composition is aerosolized into a finedroplet mist and spread across the nasal mucosa of the subject. Thedosage frequency of the nasal spray composition may vary depending uponpersonal or medical needs of the subject. Generally, dosage frequenciesmay range from about once per day, per nostril to about four timesdaily. A typical dose may contain, for example, two sprays per nostrilBID.

The following examples illustrate certain specific embodiments of theinvention and are not meant to limit the scope of the invention.

Example 1 Components, Formulation, Manufacture of BepotastineBesilate/Corticosteroid Nasal Spray Using Fluticasone Propionate as aNon-Limiting Exemplary Corticosteroid

Bepotastine besilate is a white to off-white, odorless, crystallinepowder. The bepotastine drug substance physiological mode of action isinhibition of histamine H₁ receptors to relieve typical symptomsassociated with allergic rhinitis. The water content, solubility,particle size distribution and hydration state of the bepotastine drugsubstance have no impact on the performance or manufacturability of thebepotastine besilate nasal spray suspensions. The bepotastine drugsubstance is a non-hygroscopic white crystalline powder that dissolvesreadily in the nasal spray formulation vehicle.

Fluticasone propionate is a white to off-white, crystalline synthetictrifluorinated corticosteroid used to treat inflammatory symptomsrelated to asthma and allergic rhinitis. For the drug products,fluticasone propionate is practically insoluble in water and remains ina suitably sized particle form in the aqueous suspension.

The following table lists the excipients found in the clinicalformulations (including placebo), as well as the applicable compendialgrade and primary function for each of the excipient components for eachof the nasal spray drug products. All excipient components listed arecompendial; there are no new excipient raw materials.

Excipients for Bepotastine Besilate/Fluticasone Propionate Nasal Sprays

Excipients Primary Function AVICEL ® CL-611 (microcrystalline SuspendingAgent/Viscosity cellulose and carboxymethyl Enhancing Agent cellulosesodium), NF Polysorbate 80, NF Suspending Agent Dibasic Sodium PhosphateHeptahydrate, Buffer USP Sodium Chloride, USP Tonicity Agent EdetateDisodium, USP Chelating Agent Benzalkonium Chloride, NF/USP Preservative2N Sodium Hydroxide, NF pH Adjuster 1N Hydrochloric Acid, NF pH AdjusterPurified Water, USP Solvent

For the vehicle formulation, the phosphate buffer was chosen because ofits good buffer capacity at the target pH of 6.4, as well ascompatibility with the drug substances.

Sodium chloride was added primarily as a tonicity agent to maintain theosmolality of the product at 275-400 mOsm/kg. The AVICEL® CL-611(microcrystalline cellulose with carboxymethyl cellulose) andpolysorbate 80 were added as agents to maintain the fluticasonepropionate particles suspended in the aqueous matrix. The EDTA in theformulation was added as a chelating agent.

The preservative, benzalkonium chloride (BAK), at a concentration of0.200 mg/mL, was selected because of its long history as a preservativein other nasal formulations. BAK has also been shown to be compatiblewith the bepotastine drug substance in previous ophthalmic stabilitystudies. The BAK at this concentration has been demonstrated to be aneffective preservative.

In one embodiment, the bepotastine/fluticasone nasal spray drug productswere delivered in a suspension form through a nasal spray pump.

The bepotastine besilate drug substance has been previously formulatedand marketed as an ophthalmic solution for ocular itching by ISTAPharmaceuticals, Inc. in the U.S. under the BEPREVE® brand name.

Fluticasone propionate has been previously formulated for the treatmentof symptoms associated with allergic rhinitis in commercial nasal spraysuspension forms (e.g., FLONASE®, GlaxoSmithKline). The fluticasoneactive ingredient is insoluble in water, as such it would necessitate itto be in a suspension form for administration through a nasal spraypump. The use of microcrystalline cellulose and carboxymethyl cellulose(AVICEL® CL 611) maintained the fluticasone particles evenly distributedwithin the suspension matrix. The solid fluticasone particles weremilled to an appropriately small particle size to further optimize thepharmaceutical action of fluticasone propionate.

In one embodiment, the bepotastine/fluticasone nasal sprays wereadministered topically to the nasal passages via a metered dose spraypump. The solubilized bepotastine in aqueous solution and/or thefluticasone propionate in suspension comes in contact with the nasalmucosa, where both can subsequently penetrate into the surroundingtissues and vessels and elicit a pharmaceutical effect.

The pH of the bepotastine/fluticasone nasal spray suspensions wereoptimized to a target pH of 6.4 with the phosphate buffer. The target pHin phosphate buffer maintained the chemical stability of bothbepotastine besilate and fluticasone propionate. The pH was within therange of the maximum octanol-water partition coefficient, which ispredicted to give the optimal conditions for the molecule to penetratethrough cell membranes.

To ensure manufacture of a homogeneous suspension, AVICEL® CL-611 wasdispersed in solution prior to the addition of the other components.This was accomplished by first mixing approximately 80% of the totalpurified water for the batch with AVICEL® using a high shear mixer orhomogenizer. AVICEL® contains both soluble (carboxymethyl cellulose) andinsoluble (microcrystalline cellulose) components that interact witheach other and water to form a stable suspension matrix. AVICEL® wasadded before any other components so as to not compromise the stabilityand rheological properties of the suspension matrix.

After AVICEL® dispersion, the fluticasone was dispersed as a slurry intothe AVICEL® and mixed with the high shear mixer or homogenizer. The saltexcipients were then added while mixing continuously to ensure fulldissolution of ingredients. Bepotastine besilate was then added to thesolution and the pH was adjusted with sodium hydroxide or hydrochloricacid. Following pH adjustment, benzalkonium chloride was added and afinal pH step was performed to ensure the pH was 6.4. Purified water wasadded to the final q.s. weight.

Selection of the manufacturing process was a function of therequirements and characteristics of the formulation and the dosage form,specifically that the product was a non-sterile aqueous suspension,which in one embodiment is dosed with a standard metered dose nasalspray pump.

Example 2 Composition of Placebo and Active Concentrations ofBepotastine Besilate Nasal Spray

2.0% 4.0% 6.0% Placebo (% (% (% Ingredient Function (% w/v) w/v) w/v)w/v) Bepotastine Besilate Active — 2.00 4.00 6.00 CorticosteroidAntiinflammatory — 0.05 0.05 0.05 Citric Acid, USP Buffer 0.10 0.10 0.100.10 Sodium Phosphate Buffer 0.70 0.70 0.70 0.70 Dibasic BufferHeptahydrate, USP Sodium Chloride, USP Tonicity Agent 0.65 0.35 0.200.10 Sucralose, USP Taste Masking 0.10 0.10 0.10 0.10 Agent Sorbitol,USP Taste Masking 0.35 0.35 0.35 0.35 Agent HydroxypropylmethylViscosity Agent 0.10 0.10 0.10 0.10 Cellulose (E4M), USP BenzalkoniumPreservative 0.005 0.005 0.005 0.005 Chloride, NF/USP 2N Sodium pHAdjuster pH adjustment to 6.8 Hydroxide, NF Purified Water Solvent q.s.to 100% of volume

The compositions in the table above (Example 2) failed to pass the USP51 Preservative Efficacy Test.

Example 3 Composition of Placebo and Active Concentrations ofBepotastine Besilate Nasal Spray

Component and Qualify Standard (and Grade, Placebo 2% 4% 6% ifapplicable) Function (% w/v) (% w/v) (% w/v) (% w/v) BepotastineBesilate Active — 2.00 4.00 6.00 Corticosteroid Antiinflammatory — 0.050.05 0.05 Citric Acid Buffer 0.10 0.10 0.10 0.10 Monohydrate, USPDibasic Sodium Buffer 0.70 0.70 0.70 0.70 Phosphate Heptahydrate, USPSodium Chloride, USP Tonicity Agent 0.70 0.40 0.30 0.20 Sucralose, NFTaste Masking 0.10 0.10 0.10 0.10 Agent Hydroxypropylmethyl ViscosityAgent 0.10 0.10 0.10 0.10 Cellulose (E4M), USP Edetate Disodium, USPChelating Agent 0.02 0.02 0.02 0.02 Benzalkonium Chloride NF/USPPreservative 0.0125 0.0125 0.0125 0.0125 2N Sodium Hydroxide, pHAdjuster pH adjustment to 6.8 NF Purified Water, USP Solvent q.s. to100% of volume

The compositions in the table above (Example 3) successfully passed theUSP 51 Preservative Efficacy Test; without being held to a specifictheory, this was likely due to the increased concentration ofbenzalkonium chloride in Example 3 (from 0.005% BAK in formulation 1versus 0.0125% in Example 3) and/or the presence of EDTA in thisformulation.

Example 4 Taste Making Agents

A laboratory study was performed to identify ingredients that couldempirically mask the bitter taste of the bepotastine besilate activeingredient. A surrogate bitterness model was used to evaluate theability of each or a combination of the ingredients to mask the bittertaste (data not shown). For these experiments, caffeine was used as thesurrogate bitter agent and mixed with formulation ingredients such assorbitol and sucralose; salt; citrate and phosphate buffers; and orange,tangerine, and lemon flavoring agents. Based on the taste results of theformulation matrix, sucralose and sorbitol had the largest impact onbitterness as compared to the other ingredients.

Bepotastine and a corticosteroid may be formulated as a suspension.AVICEL® CL-611, RC-591 are strong suspending agents/viscosity enhancingagents and may be added whether the active is soluble and thus does notrequire a suspension (e.g., bepotastine without a corticosteroid) or isless soluble and thus does require a suspension (e.g., bepotastine witha corticosteroid, e.g., fluticasone). The suspensions were thixotropic,and immediately liquefied upon even slight movement, as in removal foruse. According to the manufacturer (FMC), AVICEL® CL-611 is similar toAVICEL® RC-591. AVICEL® CL-611 is more compatible with a higherconcentration of salts in solution, while the viscosity and suspensionproperties of AVICEL® RC-591 are more sensitive to the amount of saltsin solution. AVICEL® CL-611 also imparts a physical property ofviscosity, so is considered as both a suspending agent and a viscosityenhancing agent.

Example 5 Compositions Including Bepotastine Besilate and aCorticosteroid Concentrations of Ingredients of Nasal Spray IncludingFluticasone Propionate

Component % w/v AVICEL ® RC-591 1.20% Fluticasone propionate 0.05%Polysorbate 80 0.01% Citric Acid Monohydrate 0.10% Sodium PhosphateDibasic 0.70% Heptahydrate Bepotastine Besilate 3.00% Sodium Chloride0.60% EDTA 0.02% BAK 0.0125%  2N NaOH pH 5.0 to 7.0

Concentrations of Ingredients of Nasal Spray Including Budesonide

Component % w/v AVICEL ® RC-591 1.20% Budesonide Free Acid 0.05%Polysorbate 80 0.01% Citric Acid Monohydrate 0.10% Sodium PhosphateDibasic 0.70% Heptahydrate Bepotastine Besilate 3.00% Sodium Chloride0.60% EDTA 0.02% BAK 0.0125%  2N NaOH pH 5.0 to 6.0

Concentrations of Ingredients of Nasal Spray Including Mometasone

Component % w/v AVICEL ® RC-591 1.20% Mometasone Furoate Monohydrate0.05% Polysorbate 80 0.01% Citric Acid Monohydrate 0.10% SodiumPhosphate Dibasic 0.70% Heptahydrate Bepotastine Besilate 3.00% SodiumChloride 0.60% EDTA 0.02% BAK 0.0125%  2N NaOH pH 4.0 to 5.5

Concentrations of Ingredients of Nasal Spray Including Triamcinolone

Component % w/v AVICEL ® CL-611 2.00% Triamcinolone Acetonide 0.055% Polysorbate 80 0.015%  Sodium Citrate 0.40% Bepotastine Besilate 4.00%Sodium Chloride 0.30% EDTA 0.02% Benzalkonium Chloride 0.02% 2N NaOH pH5.0 to 6.0

Concentrations of Ingredients of Nasal Spray Including Beclomethasone

Component % w/v AVICEL ® CL-611 2.00% Beclomethasone Dipropionate 0.05%Polysorbate 80 0.015%  Sodium Citrate 0.40% Bepotastine Besilate 4.00%Sodium Chloride 0.30% EDTA 0.02% Benzalkonium Chloride 0.02% 2N NaOH pH5.0 to 6.8Polysorbate 80 and AVICEL® RC-591, CL-611 may be used as suspendingagents without adding any viscosity agent and are used to maintainfluticasone and other steroids in suspension.

Using bepotastine/fluticasone formulation development as a non-limitingexample only, formulation was as follows. The pH of thebepotastine/fluticasone nasal spray suspensions were optimized to atarget pH of 6.4 with the phosphate buffer. The target pH in phosphatebuffer was important in maintaining the chemical stability of bothbepotastine and fluticasone. The pH was also important for bepotastinesince this pH is within the range of the maximum octanol-water partitioncoefficient, which is predicted to give the best conditions for themolecule to penetrate through cell membranes.

Chemical stability studies were performed to determine if theformulation would likely achieve a commercially practical shelf-life.Studies were performed at 25° C. and 40° C. in moisture impermeableamber glass bottles. The 4-month stability results at elevatedtemperature demonstrated that the formulation would likely be stable atroom temperature for a commercially practical shelf life period (datashown below):

Combination Placebo Stability Results 25° C./40% RH

Item Initial 2 Months 4 Months Description: Product Pass Pass PassAppearance Pass Pass Pass (White to straw colored suspension)Bepotastine Besilate Negative NA NA Identification Negative (Presence ofbepotastine peak) Bepotastine Besilate Assay NA NA NA (90-110% of LabelAmount) Ethyl Ester Impurity NA NA NA (Not More Than 1.0%) Any OtherIndividual NA NA NA Impurity (Not More Than 0.5%) Bepotastine Total NANA NA Impurities (Not More Than 2.0%) Bepotastine Optical Isomer NA NANA (% of Active) (Not More Than 1.0%) Fluticasone Propionate Negative NANA Identification Negative (RRT = 0.95-1.05 is a positive indicator)Fluticasone Propionate NA NA NA Assay (90-115% of Label Amount)Fluticasone Related Any NA NA NA Individual Impurity (Report)Fluticasone Related Total NA NA NA Impurities (Report) BenzalkoniumChloride 96 98 96 (BAK) Assay 98 97 97 (80-125% of Theoretical Amount)pH 6.4 6.4 6.4 (6.3-7.3) 6.4 6.4 6.4 Osmolality 359 363 367 (Report) 359367 365 EDTA 101 100 99 (80-120% of Theoretical 104 101 99 Amount)Storage Condition: 25° C. ± 5° C., 40% ± 5% RH (Upright) Product Size:15 mL Bottle: Amber glass Pump: N/A (Crimped butyl stopper) NA = NotApplicable

Combination Placebo Stability Results 40° C./20% RH

Item Initial 2 Months 4 Months Description: Product Pass Pass PassAppearance (White to straw Pass Pass Pass colored suspension)Bepotastine Besilate Negative NA NA Identification Negative (Presence ofbepotastine peak) Bepotastine Besilate Assay NA NA NA (90-110% of LabelAmount) Ethyl Ester Impurity NA NA NA (Not More Than 1.0%) Any OtherIndividual Impurity NA NA NA (Not More Than 0.5%) Bepotastine TotalImpurities NA NA NA (Not More Than 2.0%) Bepotastine Optical Isomer (%NA NA NA of Active) (Not More Than 1.0%) Fluticasone Propionate NegativeNA NA Identification Negative (RRT = 0.95-1.05 is a positive indicator)Fluticasone Propionate Assay NA NA NA (90-115% of Label Amount)Fluticasone Related Any NA NA NA Individual Impurity (Report)Fluticasone Related Total NA NA NA Impurities (Report) BenzalkoniumChloride 96 97 96 (BAK) Assay 98 96 97 (80-125% of Theoretical Amount)pH 6.4 6.4 6.4 (6.3-7.3) 6.4 6.4 6.4 Osmolality 359 364 363 (Report) 359362 371 EDTA 101 99 97 (80-120% of Theoretical 104 100 98 Amount)Storage Condition: 40° C. ± 5° C., 20% RH ± 5% (Upright) Product Size:15 mL Bottle: Amber glass Pump: N/A (Crimped butyl stopper) NA = NotApplicable

Fluticasone/Bepotastine Combination Stability Results 25° C./40% RH

Storage Condition: 25° C. ± 5° C., Bottle: Amber glass (SGD, 40% RH ± 5%France) (Upright) Pump: Aptar VP7A/100 μL Product Size: 15 mL 2 4 ItemInitial Months Months Description: Product Pass Pass Pass AppearancePass Pass Pass (White to straw colored suspension) Bepotastine BesilatePositive NA NA Identification Positive NA NA (Presence of bepotastinepeak) Bepotastine Besilate 102 102 100 Assay (90-110% of 102 101 98Label Amount) Ethyl Ester Impurity 0.5 0.2 0.1 (Not More Than 1.0%) 0.40.2 0.1 Any Other Individual ND ND ND Impurity ND ND ND (Not More Than0.5%) Bepotastine Total 0.5 0.2 0.1 Impurities 0.4 0.2 0.1 (Not MoreThan 2.0%) Bepotastine Optical 0.1 0.1 0.1 Isomer (% of Active) 0.1 0.10.1 (Not More Than 1.0%) Fluticasone Propionate Positive NA NAIdentification Positive NA NA (RRT = 0.95-1.05 is a positive indicator)Fluticasone Propionate 101 99 101 Assay (90-115% of 100 99 102 LabelAmount) Fluticasone Related ND <LOQ 0.1 (Compound E) Any Individual NDND ND Impurity (Report) Fluticasone Related ND <LOQ 0.1 Total ImpuritiesND ND ND (Report) Benzalkonium Chloride 99 99 100 (BAK) Assay (80-125%of 100 100 98 Theoretical Amount) pH 6.4 6.4 6.4 (6.3-7.3) 6.4 6.4 6.4Osmolality 347 349 352 (Report) 348 347 348 EDTA 101 101 98 (80-120% of104 102 98 Theoretical Amount) NA = Not Applicable; ND = Not Detected;LOQ = Limit of Quantitation (0.08%)

Fluticasone/Bepotastine Stability Results 40° C./20% RH

Storage Condition: 40° C. ± 5° C., Bottle: Amber glass (SGD, 20% RH ± 5%France) (Upright) Pump: Aptar VP7A/100 μL Product Size: 15 mL 2 4 ItemInitial Months Months Description: Product Pass Pass Pass AppearancePass Pass Pass (White to straw colored suspension) Bepotastine BesilatePositive NA NA Identification Positive NA NA (Presence of bepotastinepeak) Bepotastine Besilate 102 101 104 Assay (90-110% of 102 99 100Label Amount) Ethyl Ester Impurity 0.5 ND ND (Not More Than 1.0%) 0.4 NDND Any Other Individual ND ND ND Impurity ND ND ND (Not More Than 0.5%)Bepotastine Total 0.5 ND ND Impurities 0.4 ND ND (Not More Than 2.0%)Bepotastine Optical 0.1 0.2 0.3 Isomer (% of Active) 0.1 0.2 0.3 (NotMore Than 1.0%) Fluticasone Propionate Positive NA NA IdentificationPositive NA NA (RRT = 0.95-1.05 is a positive indicator) FluticasonePropionate 101 100 102 Assay (90-115% of 100 99 102 Label Amount)Fluticasone Related ND ND 0.1, 0.1 (Unknown Any Individual ND ND RRT =0.37) Impurity (Report) 0.1, (Unknown RRT = 0.39) Fluticasone Related NDND 0.2 Total Impurities ND ND 0.1 (Report) Benzalkonium Chloride 99 99101 (BAK) Assay (80-125% of 100 100 100 Theoretical Amount) pH 6.4 6.46.4 (6.3-7.3) 6.4 6.4 6.4 Osmolality 347 359 348 (Report) 348 351 350EDTA 101 98 94 (80-120% of 104 98 92 Theoretical Amount) NA = NotApplicable; ND = Not Detected

The formulations are as follows. Formulation 1 and placebo, withconcentration ranges and for a specific embodiment, respectively, arepresented in the following two tables: Formulation 1 and placebo(concentration ranges)

Active Placebo Ingredient Function (% w/v) (% w/v) Bepotastine BesilateActive  0.5-8.00 — Fluticasone Anti- 0.01-1.00 — Propionate inflam-matory Hydroxypropyl- Viscosity 0.01-1.00 0.01-1.00 methyl AgentCellulose (E15LV) Polysorbate 80 Suspending 0.005-0.050 0.005-0.050Agent Citric Acid Buffer 0.10-1.00 0.10-1.00 Monohydrate SodiumPhosphate Buffer 0.10-1.00 0.10-1.00 Dibasic Heptahydrate Sodiumchloride Tonicity 0.9 with 0.5% active 0.70 Agent 0.4 with 2.00%- 3.00%active 0.3 with 4.00% active 0.2 with 6.00% active 0.1 with 8.00% activeSucralose Taste 0.01-1.00 0.01-1.00 Masking Agent EDTA, USP Chelating0.005-0.100 0.005-0.100 Agent Benzalkonium Preser- 0.002-0.2000.002-0.200 Chloride, NF/USP vative 2N NaOH pH pH to 4.0-9.0 pH 4.0-9.0Adjuster Purified Water Solvent q.s. to 100% q.s. to 100% of volume ofvolume

Formulation 1 and Placebo (Specific Concentrations)

Active Placebo Ingredient Function (% w/v) (% w/v) Bepotastine BesilateActive 4.00 — Fluticasone Anti- 0.05 — Propionate inflam- matoryHydroxypropyl- Viscosity 0.10 0.10 methyl Agent Cellulose (E15LV)Polysorbate 80 Suspending 0.01 0.01 Agent Citric Acid Buffer 0.10 0.10Monohydrate Sodium Phosphate Buffer 0.70 0.70 Dibasic HeptahydrateSodium chloride Tonicity 0.30 0.70 Agent Sucralose Taste Making 0.100.10 Agent EDTA, USP Chelating 0.02 0.02 Agent Benzalkonium Preser-0.0125 0.0125 Chloride, NF/USP vative 2N NaOH pH pH to 6.8 pH 6.8Adjuster Purified Water solvent q.s. to 100% q.s. to 100% of volume ofvolumeFormulation 2 and placebo, with concentration ranges and for a specificembodiment, respectively, are presented in the following two tables:

Formulation 2 and Placebo (Ranges)

Active Placebo Ingredient Function (% w/v) (% w/v) Bepotastine BesilateActive  0.5-8.00 — Fluticasone Anti- 0.01-1.00 — Propionate inflam-matory AVICEL ® Suspending 0.5-2.5 0.5-2.5 CL-611, RC- Agent/ 581, orRC-591 Viscosity (blend of micro- Enhancing crystalline cellulose Agentand carboxymethyl cellulose sodium), NF Polysorbate 80, Suspending0.005-0.050 0.005-0.050 NF Agent Dibasic Sodium Buffer 0.10-1.000.10-1.00 Phosphate Hepta- hydrate, USP Sodium Chloride, Tonicity 0.9with 0.5% active 0.80 USP Agent 0.4 with 2.00%- 3.00% active 0.3 with4.00% active 0.2 with 6.00% active 0.1 with 8.00% active EdetateDisodium, Chelating 0.005-0.100 0.005-0.100 USP Agent BenzalkoniumPreser- 0.002-0.200 0.002-0.200 Chloride, NF/USP vative 2N Sodium pH pHpH Hydroxide, NF Adjuster adjustment adjustment to 4.0-9.0 to 4.0-9.0Purified Water, Solvent q.s. to 100% q.s. to 100% USP

Formulation 2 and Placebo (Specific)

Active Placebo Ingredient Function (% w/v) (% w/v) Bepotastine BesilateActive 4.00 — Fluticasone Anti- 0.05 — Propionate inflam- matoryAVICEL ® Suspending 2.00 2.00 CL-611 (blend of Agent/ microcrystallineViscosity cellulose and Enhancing carboxymethyl Agent cellulose sodium),NF Polysorbate 80, Suspending 0.015 0.015 NF Agent Dibasic Sodium Buffer0.70 0.70 Phosphate Hepta- hydrate, USP Sodium Chloride, Tonicity 0.300.80 USP Agent Edetate Disodium, Chelating 0.02 0.02 USP AgentBenzalkonium Preser- 0.020 0.020 Chloride, NF/USP vative 2N Sodium pH pHpH Hydroxide, NF Adjuster adjustment adjustment to 6.4 to 6.4 PurifiedWater, Solvent q.s. to 100% q.s. to 100% USP

Formulation 3 and Placebo (Specific)

Active Placebo Ingredient Function (% w/v) (% w/v) Bepotastine BesilateActive 3.00 — Fluticasone Anti- 0.05 — Propionate inflam- matoryAVICEL ® Suspending 1.20 1.20 RC-591 Agent/ Viscosity Enhancing AgentPolysorbate 80, Suspending 0.01 0.01 NF Agent Citric Acid Buffer 0.100.10 Monohydrate Dibasic Sodium Buffer 0.70 0.70 Phosphate Heptahydrate,USP Sodium Chloride, Tonicity 0.60 0.70 USP Agent Edetate Disodium,Chelating 0.02 0.02 USP Agent Benzalkonium Preser- 0.0125 0.0125Chloride, NF/USP vative 2N Sodium pH pH pH Hydroxide, NF Adjusteradjustment adjustment to 5-7 to 5-7 Purified Water, Solvent q.s. to 100%q.s. to 100% USP

Formulation 4 and Placebo (Specific)

Active Placebo Ingredient Function (% w/v) (% w/v) Bepotastine BesilateActive 3.00 — Budesonide Free Anti- 0.05 — Acid inflam- matory AVICEL ®Suspending 1.20 1.20 RC-591 Agent/ Viscosity Enhancing Agent Polysorbate80, Suspending 0.01 0.01 NF Agent Citric Acid Buffer 0.10 0.10Monohydrate Dibasic Sodium Buffer 0.70 0.70 Phosphate Heptahydrate, USPSodium Chloride, Tonicity 0.60 0.70 USP Agent Edetate Disodium,Chelating 0.02 0.02 USP Agent Benzalkonium Preser- 0.0125 0.0125Chloride, NF/USP vative 2N Sodium pH pH pH Hydroxide, NF Adjusteradjustment adjustment to 5.0-6.0 to 5.0-6.0 Purified Water, Solvent q.s.to 100% q.s. to 100% USP

Formulation 5 and Placebo (Specific)

Active Placebo Ingredient Function (% w/v) (% w/v) Bepotastine BesilateActive 3.00 — Mometasone Furoate Anti- 0.05 — Monohydrate inflam- matoryAVICEL ® Suspending 1.20 1.20 RC-591 Agent/ Viscosity Enhancing AgentPolysorbate 80, Suspending 0.01 0.01 NF Agent Citric Acid Buffer 0.100.10 Monohydrate Dibasic Sodium Buffer 0.70 0.70 Phosphate Hepta-hydrate, USP Sodium Chloride, Tonicity 0.60 0.70 USP Agent EdetateDisodium, Chelating 0.02 0.02 USP Agent Benzalkonium Preser- 0.01250.0125 Chloride, NF/USP vative 2N Sodium pH pH pH Hydroxide, NF Adjusteradjustment adjustment to 4.0-5.5 to 4.0-5.5 Purified Water, Solvent q.s.to 100% q.s.to 100% USPThe associated antimicrobial preservative effectiveness test data foreach of Formulation 1 and Formulation 2, the 12 month stability data atboth 25° C. and 40° C. for Formulation 1, and the 4 month stability dataat both 25° C. and 40° C. for Formulation 2, were determined to providesatisfactory preservative efficacy, and be stable during a commerciallypractical shelf life period (data shown below).

The preservative utilized in all of the bepotastine/fluticasone nasalspray formulations was benzalkonium chloride, which historically has hada long history as an effective preservative in topical preparationsincluding ophthalmic drops and nasal sprays. The compatibility ofbenzalkonium chloride and bepotastine has been previously confirmed(data not shown). Benzalkonium chloride and fluticasone have also beenshown to be compatible in the commercial preparations of fluticasonepropionate suspension, such as FLONASE®. To determine the antimicrobialeffectiveness of the BAK in each of the different nasal sprayformulations, a study was performed for antimicrobial preservativeeffectiveness testing per USP <51>.

The drug products met the USP <51> criteria for Category 2 drugproducts. The verification (neutralization qualification) for theantimicrobial preservative effectiveness testing was also performed.

Log₁₀ Reduction Results for Placebo Formulation

LOG REDUCTION 0 7 14 28 Organism HOUR DAY DAY DAY Aspergillusbrasiliensis (niger) 0.07 ~4.15 ~4.27 >4.27 Candida albicans0.77 >4.45 >4.45 >4.45 Escherichia coli >4.11 >4.11 >4.11 >4.11Staphylococcus aureus >4.46 >4.46 >4.46 >4.46 Pseudomonas aeruginosa~4.23 >4.23 >4.23 >4.23

Log₁₀, Reduction Results for Bepotastine/Fluticasone CombinationFormulation

LOG REDUCTION 0 7 14 28 Organism HOUR DAY DAY DAY Aspergillusbrasiliensis (niger) 0.06 0.24 0.62 1.22 Candida albicans −0.04 1.192.55 ~4.02 Escherichia coli >4.11 >4.11 >4.11 >4.11 Staphylococcusaureus 1.31 >4.46 >4.46 >4.46 Pseudomonas aeruginosa >4.23 >4.23 >4.23>4.23

Log₁₀ Reduction Results for Fluticasone Propionate Formulation

LOG REDUCTION 0 7 14 28 Organism HOUR DAY DAY DAY Aspergillusbrasiliensis (niger) 0.18 >4.27 >4.27 >4.27 Candida albicans1.49 >4.45 >4.45 >4.45 Escherichia coli >4.11 >4.11 >4.11 >4.11Staphylococcus aureus >4.46 >4.46 >4.46 >4.46 Pseudomonasaeruginosa >4.23 >4.23 >4.23 >4.23

Log₁₀, Reduction Results for Bepotastine Besilate Formulation

LOG REDUCTION 0 7 14 28 Organism HOUR DAY DAY DAY Aspergillusbrasiliensis (niger) 0.17 0.26 0.66 1.03 Candida albicans 0.00 0.93 2.43~4.08 Escherichia coli >4.11 >4.11 >4.11 >4.11 Staphylococcusaureus >0.73 >4.46 >4.46 >4.46 Pseudomonas aeruginosa >4.23 >4.23 >4.23>4.23Bepotastine was monitored for impurities during stability evaluation.The only impurity found was the ethyl ester precursor of bepotastinefrom bepotastine synthesis. Upon solvation and aging in the formulation,the ethyl ester group on the bepotastine molecule is hydrolyzed to formthe bepotastine drug. The results are shown below:

Formulation 2 Stored at 40° C. (Percent of Formulated Amount)

Bepotastine Besilate Fluticasone Propionate Initial 102%, 102% 101%,100% 2 months 101%, 99% 100%, 99% 4 months 104%, 100% 102%, 102%

Formulation 2 Stored at 25° C. (Percent of Formulated Amount)

Bepotastine Besilate Fluticasone Propionate Initial 102%, 102% 101%,100% 2 months 102%, 101%  99%, 99% 4 months 100%, 98% 101%, 102%

AVICEL® CL-611 at a concentration of 2.00% was used for all subsequentevaluations in both bepotastine (with besilate salt) combined withcorticosteroid formulations.

The formulations and the associated AET data and stability data weredetermined to provide satisfactory preservative efficacy and stabilityduring a commercially practical shelf life period.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

1-68. (canceled)
 69. A pharmaceutical composition comprising at leastone corticosteroid as a free form, pharmaceutically acceptable salt,solvate, or physiologically functional derivative thereof, andbepotastine as a free base, pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof, the bepotastine at aconcentration from 0.5% w/v to 8.00% w/v inclusive, with at least onepharmaceutically compatible excipient, the composition formulated as anasal spray.
 70. The composition of claim 69 wherein the bepotastineconcentration is from 2.00% w/v to 4.00% w/v inclusive.
 71. Thecomposition of claim 69 wherein the excipient is a viscosity enhancingagent and is hydroxypropylmethyl cellulose (HPMC).
 72. The compositionof claim 69 further comprising a preservative.
 73. The composition ofclaim 72 wherein the preservative is benzalkonium chloride.
 74. Thecomposition of claim 69 further comprising at least one pharmaceuticallycompatible buffer, a tonicity agent, a chelating agent, and an optionaltaste-masking agent.
 75. The composition of claim 74 wherein thepharmaceutically compatible buffer is each of a phosphate buffer and acitrate buffer.
 76. The composition of claim 74 wherein the tonicityagent is sodium chloride.
 77. The composition of claim 74 wherein thechelating agent is ethylenediamine tetraacetic acid.
 78. The compositionof claim 69 wherein the excipient is a suspending agent comprising ablend of microcrystalline cellulose and carboxymethyl cellulose(AVICEL®) and/or polyoxyethylene (20) sorbitan monooleate (polysorbate80).
 79. The composition of claim 69 wherein the excipient is asuspending agent comprising HPMC, AVICEL®, and polysorbate
 80. 80. Thecomposition of claim 78 or claim 79 wherein the concentration of thesuspending agent is 0.5% w/v-2.5% w/v for AVICEL® and is 0.005%w/v-0.050% w/v for polysorbate
 80. 81. The composition of claim 74wherein the optional taste-making agent is (tri)sodium citrate, sodiumcitrate, sodium chloride, sodium bicarbonate, a polyol sweetener, a highintensity sweetener, and/or a flavoring agent.
 82. The composition ofclaim 74 wherein the optional taste-masking agent is sucralose.
 83. Thecomposition of claim 69 where the pharmaceutically acceptablebepotastine salt is besilate.
 84. The composition of claim 69 whereinthe corticosteroid concentration is from 0.01% w/v to 1% w/v inclusive,and the corticosteroid is selected from the group consisting ofbeclomethasone, beclomethasone dipropionate, mometasone furoatemonohydrate, fluticasone propionate, fluticasone furoate, triamcinolone,triamcinolone acetonide, budesonide, budesonide free acid, ciclesonide,beclomethasone sodium, dexamethasone sodium, prednisolone acetate, andmixtures thereof.
 85. A pharmaceutical composition comprisingbepotastine besilate and a corticosteroid free form, pharmaceuticallyacceptable salt, solvate, or physiologically functional derivativethereof, dibasic sodium phosphate heptahydrate, sodium chloride, edetatedisodium, benzalkonium chloride, and one of either: a blend ofmicrocrystalline cellulose and carboxymethyl cellulose (AVICEL®) and/orpolyoxyethylene (20) sorbitan monooleate (polysorbate 80), orhydroxypropylmethyl cellulose (HPMC), citric acid monohydrate, and ataste making agent.
 86. The composition of claim 85 wherein theconcentration of bepotastine besilate is 0.5% w/v to 8.00% w/v; theconcentration of corticosteroid is 0.01% w/v to 1.00% w/v; theconcentration of dibasic sodium phosphate heptahydrate is 0.10% w/v to1.00% w/v; the concentration of sodium chloride is 0.9% w/v with 0.5%bepotastine, 0.4% w/v with 2.00%-3.00% bepotastine, 0.3% w/v with 4.00%bepotastine, 0.2% w/v with 6.00% bepotastine, 0.1% w/v with 8.00%bepotastine; the concentration of edetate disodium is 0.005% w/v to0.100% w/v; the concentration of benzalkonium chloride is 0.002% w/v to0.200% w/v; and if used, AVICEL® is AVICEL® CL-611 at a concentration of0.5% w/v to 2.5% w/v, and the concentration of polysorbate 80 is 0.005%w/v to 0.050% w/v; or if used, the concentration of HPMC is 0.01% w/v to1.00% w/v, the concentration of citric acid monohydrate is 0.10% w/v to1.00% w/v, and the concentration of the taste-making agent is 0.01% w/vto 1.00% w/v.
 87. The composition of claim 85 wherein the concentrationof bepotastine besilate is 4.00% w/v, the concentration ofcorticosteroid is 0.05% w/v, the concentration of dibasic sodiumphosphate heptahydrate is 0.70% w/v, the concentration of sodiumchloride is 0.30% w/v, the concentration of edetate disodium is 0.020%w/v, the concentration of benzalkonium chloride is 0.020% w/v, and ifused, AVICEL® is AVICEL® CL-611 at a concentration of 2.00% w/v and theconcentration of polysorbate 80 is 0.015% w/v; or if used, HPMC is HPMCE15 LV at a concentration of 0.10% w/v, the concentration of citric acidmonohydrate is 0.10% w/v, and the taste-masking agent is sucralose andthe concentration thereof is 0.10% w/v.
 88. A kit comprising a metereddose plunger spray pump coupled with a container containing thecomposition of claim 69, and instructions for administering thecomposition using the metered dose plunger spray pump.
 89. Apharmaceutical composition comprising a pharmaceutically acceptable saltof bepotastine and at least one corticosteroid, dibasic sodium phosphateheptahydrate, sodium chloride, edetate disodium, benzalkonium chloride,a blend of microcrystalline cellulose and carboxymethyl cellulose(AVICEL®), and/or polyoxyethylene (20) sorbitan monooleate (polysorbate80).
 90. A pharmaceutical composition comprising a pharmaceuticallyacceptable salt of bepotastine and at least one corticosteroid, dibasicsodium phosphate heptahydrate, sodium chloride, edetate disodium,benzalkonium chloride, hydroxypropylmethyl cellulose (HPMC), citric acidmonohydrate, and a taste making agent.
 91. The composition of claim 89wherein the pharmaceutically acceptable salt of bepotastine is besilateand the concentration of bepotastine is 0.5% w/v to 8.00% w/v; theconcentration of corticosteroid is 0.01% w/v to 1% w/v; theconcentration of dibasic sodium phosphate heptahydrate is 0.10% w/v to1.00% w/v; the concentration of sodium chloride is 0.9% w/v with 0.5%bepotastine, 0.4% w/v with 2.00%-3.00% bepotastine, 0.3% w/v with 4.00%bepotastine, 0.2% w/v with 6.00% bepotastine, 0.1% w/v with 8.00%bepotastine; the concentration of edetate disodium is 0.005% w/v to0.100% w/v; the concentration of benzalkonium chloride is 0.002% w/v to0.200% w/v; the concentration of AVICEL® is 0.5% w/v to 2.5% w/v; andthe concentration of polysorbate 80 is 0.005% w/v to 0.050% w/v.
 92. Thecomposition of claim 90 wherein the pharmaceutically acceptable salt ofbepotastine is besilate and the concentration of bepotastine is 0.5% w/vto 8.00% w/v; the concentration of corticosteroid is 0.01% w/v to 1%w/v; the concentration of dibasic sodium phosphate heptahydrate is 0.10%w/v to 1.00% w/v; the concentration of sodium chloride is 0.9% w/v with0.5% bepotastine, 0.4% w/v with 2.00%-3.00% bepotastine, 0.3% w/v with4.00% bepotastine, 0.2% w/v with 6.00% bepotastine, 0.1% w/v with 8.00%bepotastine; the concentration of edetate disodium is 0.005% w/v to0.100% w/v; the concentration of benzalkonium chloride is 0.002% w/v to0.200% w/v; HPMC is HPMC E15 LV at a concentration of 0.01% w/v to 1.00%w/v, the concentration of citric acid monohydrate is 0.10% w/v to 1.00%w/v, and the concentration of the taste-making agent is 0.01% w/v to1.00% w/v.
 93. The composition of claim 89 wherein the concentration ofbepotastine besilate is 4.00% w/v, the concentration of corticosteroidis 0.01% w/v to 1% w/v, the concentration of dibasic sodium phosphateheptahydrate is 0.70% w/v, the concentration of sodium chloride is 0.30%w/v, the concentration of edetate disodium is 0.020% w/v, theconcentration of benzalkonium chloride is 0.020% w/v, AVICEL® is AVICEL®CL-611 at a concentration of 2.00% w/v, and the concentration ofpolysorbate 80 is 0.015% w/v.
 94. The composition of claim 90 whereinthe concentration of bepotastine besilate is 4.00% w/v, theconcentration of corticosteroid is 0.01% w/v to 1% w/v, theconcentration of dibasic sodium phosphate heptahydrate is 0.70% w/v, theconcentration of sodium chloride is 0.30% w/v, the concentration ofedetate disodium is 0.020% w/v, the concentration of benzalkoniumchloride is 0.020% w/v, HPMC is HPMC E15 LV at a concentration of 0.10%w/v, the concentration of citric acid monohydrate is 0.10% w/v, and thetaste-masking agent is sucralose and the concentration thereof is 0.10%w/v.
 95. A pharmaceutical composition comprising at least onecorticosteroid as a free form, pharmaceutically acceptable salt,solvate, or physiologically functional derivative thereof, andbepotastine as a free base, pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof, the bepotastine at aconcentration from 0.5% w/v to 8.00% w/v inclusive, and a suspendingagent interchangeable with a viscosity enhancing agent, the compositionformulated as a nasal spray.
 96. The kit of claim 88 wherein thecomposition is formulated as a nasal spray, nasal drops, nasal droplets,or combinations thereof.